Aminothiazoles and their uses

ABSTRACT

The present application describes organic compounds that are useful for the treatment, prevention and/or amelioration of diseases.

BACKGROUND

Since the discovery of penicillin, pharmaceutical companies haveproduced a number of antibacterial agents to combat a wide variety ofbacterial infections. In the past several years, there has been rapidemergence of bacterial resistance to several of these antibiotics. Themultidrug resistance among these bacterial pathogens may also be due tomutation leading to more virulent clinical isolation. Perhaps the mostdisturbing occurrence has been the acquisition of resistance tovancomycin, an antibiotic generally regarded as the agent of last resortfor serious Gram-positive infections.

This is true especially of some Gram-positive pathogen groups, such asstaphylococci, pneumococci and enterococci (S. Ewig et al.;Antibiotika-Resistenz bei Erregern ambulant erworbenerAtemwegsinfektionen (Antibiotic resistance in pathogens ofoutpatient-acquired respiratory tract infections); Chemother. J. 2002,11, 12-26; F. Tenover; Development and spread of bacterial resistance toantimicrobial agents: an overview; Clin. Infect. Dis. 2001 Sep. 15, 33Suppl. 3, 108-115) as well as Staphylococcus, Streptococcus,Mycobacterium, Enterococcus, Corynebacterium, Borrelia, Bacillus,Chlamydia, Mycoplasma, and the like.

A problem of equally large dimension is the increasing incidence of themore virulent, methicillin-resistant Staphylococcus aureas (MRSA) amongclinical isolates found worldwide. As with vancomycin resistantorganisms, many MRSA strains are resistant to most of the knownantibiotics, but MRSA strains have remained sensitive to vancomycin.However, in view of the increasing reports of vancomycin resistantclinical isolates and growing problem of bacterial resistance, there isan urgent need for new molecular entities effective against the emergingand currently problematic Gram-positive organisms.

This growing multidrug resistance has recently rekindled interest in thesearch for new structural classes of antibiotics that inhibit or killthese bacteria.

SUMMARY OF THE INVENTION

There remains a need for new treatments and therapies for bacterialinfections. There is also a need for compounds useful in the treatmentor prevention or amelioration of one or more symptoms of bacterialinfections. Furthermore, there is a need for methods for modulating theactivity of the elongation factor EF-Tu, using the compounds providedherein.

In one aspect, the invention provides a compound of formula I:

In yet another aspect, the invention provides a compound of formula II:

In still another aspect, the invention provides a compound of formulaIII:

In another aspect, the invention provides a compound of formula IV:

In another aspect, the invention provides a compound of formula V:

In another aspect, the invention provides a compound of formula VI:

In yet another aspect, the invention provides a compound of formula VII:

In another aspect, the invention provides a compound of formula VIII:

In another aspect, the invention provides a method of treating abacterial infection wherein the treatment includes administering to asubject in need thereof a pharmaceutically acceptable amount of acompound of formula I, II, III, IV, V, VI, VII or VIII, such that thebacterial infection is treated.

In another aspect, the invention provides a method of treating an EF-Tuassociated-state wherein the treatment includes administering to asubject in need thereof a pharmaceutically acceptable amount of acompound of formula I, II, III, IV, V, VI, VII or VIII, such that theEF-Tu associated state is treated.

In still another aspect, the invention provides a method of treating,inhibiting or preventing the activity of EF-Tu in a subject in needthereof, which includes administering to the subject a pharmaceuticallyacceptable amount of a compound of formula I, II, III, IV, V, VI, VII orVIII. In one embodiment, a bacterial infection is treated in a subjectin need thereof.

In another aspect, the invention provides a method of treating,inhibiting or preventing the activity of bacteria in a subject in needthereof, which includes administering to the subject a pharmaceuticallyacceptable amount of a compound of formula I, II, III, IV, V, VI, VII orVIII, wherein the compound interacts with any target in the life cycleof the bacteria. In one embodiment, the target is EF-Tu.

In another aspect, the invention provides a method of treating abacterial infection in a subject, wherein the treatment includesadministering to a subject in need thereof a pharmaceutically acceptableamount of a compound of the formula I, II, III, IV, V, VI, VII or VIII,and a pharmaceutically acceptable carrier, such that the bacterialinfection is treated.

In still another aspect, the invention provides a method of treating abacterial infection wherein the treatment includes administering to asubject in need thereof a pharmaceutically effective amount of acompound of the formula I, II, III, IV, V, VI, VII or VIII, incombination with a pharmaceutically effective amount of an additionaltherapeutic agent, such that the bacterial infection is treated. In oneembodiment, the compound of the formula I, II, III, IV, V, VI, VII orVIII and the other pharmaceutical agent are administered as part of thesame pharmaceutical composition. In another embodiment, the compound ofthe formula I, II, III, IV, V, VI, VII or VIII and the other therapeuticagent are administered as separate pharmaceutical compositions, and thecompound is administered prior to, at the same time as, or followingadministration of the other agent.

In another aspect, the invention provides a packaged bacterial infectiontreatment, comprised of formula I, II, III, IV, V, VI, VII or VIII,packaged with instructions for using an effective amount of the compoundto treat a bacterial infection.

In another aspect, the invention provides a method of treating acne insubject in need thereof, wherein the treatment includes administering tothe subject a pharmaceutically acceptable amount of a compound offormula I, II, III, IV, V, VI, VII or VIII.

In yet another aspect, the invention provides a pharmaceuticalcomposition which includes a compound of formula I, II, III, IV, V, VI,VII or VIII, and at least one pharmaceutically acceptable carrier ordiluent.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to compounds, e.g., thiopeptide compounds,and intermediates thereto, as well as pharmaceutical compositionscontaining the compounds for use in treatment of bacterial infection.This invention is also directed to the compounds of the invention orcompositions thereof as modulators of the elongation factor EF-Tu. Thecompounds are particularly useful in interfering with the life cycle ofbacteria and in treating or preventing a bacterial infection orphysiological conditions associated therewith. The present invention isalso directed to methods of combination therapy for inhibiting EF-Tuactivity in cells, or for treating or preventing a bacterial infectionin patients using the compounds of the invention or pharmaceuticalcompositions, or kits thereof.

In one aspect, the invention provides compounds of the formula I:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof;

wherein

A is selected from the group consisting of a bond, H, —(CH₂)—,—C(alkyl)₂-, —(CH₂)₁₋₈—, —[C(alkyl)₂]₁₋₈—, -(cycloalkyl)-, -(aryl)-,-(heteroaryl)-, —C(O)—, —C(O)C(O)—, —C(O)O—, —C(O)N(R^(8a))—, —S(O)₂—,—S(O)—, —S(O)₂N(R^(8a))—, —S(O)N(R^(8a))—, —C(═NR⁸)N(R^(8a))—,—C(═NR⁸)N(R^(8a))C(O)—, —C(═NR⁸)—, —C═C—C(O)—, —C═C—C(O)O—,—C═C—C(O)N(R^(8a))—;

G is absent, or selected from the group consisting of H,—[C(R^(a))(R^(b))]_(x)—,—[C(R^(a))(R^(b))]_(x)—O—[C(R^(a))(R^(b))]_(y)—,—[C(R^(a))(R^(b))]_(x)—N(R^(8a))—[C(R^(a))(R^(b))]_(y)—, -(cycloalkyl)-,-(heterocycle)-, -(aryl)-, -(heteroaryl)-;

J is selected from the group consisting of H, F, O-alkyl, N(R^(8a))₂,N⁺(R^(8a))₃, N(R^(8a))C(O)alkyl, CO₂H, C(═O)N(R^(8a))₂, CO₂-alkyl,P(O)(OH)₂, P(O)(O-alkyl)₂, and a substituted nitrogen-containingheterocycle;

R^(a) is selected from the group consisting of H, alkyl, F, CO₂H,CO₂-alkyl, —N(R¹)₂, —OR¹, —(CH₂)₀₋₄-J and —R^(4b);

R^(b) is selected from the group consisting of H, alkyl, and F;

x and y are each, independently, integers from 0-10;

R¹ is selected from —H, —C(alkyl)₂-J, —R^(4b).

R^(2a) is selected from the group consisting of H, substituted orunsubstituted alkyl, OH, OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ andN(R^(8a))₂;

R^(2b) is selected from the group consisting of absent, H and alkyl, orR^(2a) and R^(2b) may together form ═O or ═NH;

R³ an R¹² are each, independently, selected from the group consisting ofH, halogen, OR^(4b), -G-J, and N(R^(8a))₂;

R^(4a) is selected from the group consisting of H, and alkyl;

R^(4b) is selected from the group consisting of alkyl and—(CH₂—CH₂—O—)_(n)—R⁹, wherein n is an integer equal to or averaging1-60,000, e.g., 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000,20,000, 30,000, 40,000, 50,000, 60,000;

R⁵ is selected from the group consisting of H, alkyl, and R^(4b);

R⁸ is selected from the group consisting of H, CN, NO₂, alkyl,cycloalkyl, and SO₂-alkyl;

R^(8a) is absent, or selected from the group consisting of H, -(alkyl)-,-(cycloalkyl)-, C(alkyl)₂-J, —R^(4b), wherein R^(8a) can also cyclizewith the atom to which R^(8a) is bonded to form a 3, 4, 5, 6 or7-membered ring that is aromatic or non-aromatic and may contain one ormore heteroatoms, wherein the ring may be further substituted one ormore times with substitutents that are the same or different; and

R⁹ is selected from the group consisting of H, alkyl and CH₂CO₂H.

In one embodiment of formula I, R^(2b), R^(4b) and R⁵ are H, and R^(4a)is CH₃. In another embodiment of formula I, R^(2b), R^(4b) and R⁵ are H,R^(4a) is CH₃, and R¹² is CH₂—O—CH₃.

In another embodiment, formula I is represented by a compound of formulaII:

and pharmaceutically acceptable salts thereof.

In another aspect, the invention provides a compound of the formula III:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof;

wherein

R^(2a), R^(2b), R³, R^(4a), R^(4b), R⁵, R¹², A, G and J have themeanings set forth for formula I;

and ring L is selected form the group consisting of cycloalkyl,heterocycle, aryl and heteroaryl, all of which may be further optionallysubstituted with -A-G-J.

In one embodiment of formula III, R^(2b), R^(4b) and R⁵ are H, andR^(4a) is CH₃. In another embodiment of formula III, R^(2b), R^(4b) andR⁵ are H, R^(4a) is CH₃, and R¹² is CH₂—O—CH₃.

In another embodiment, formula III is represented by a compound offormula IV:

and pharmaceutically acceptable salts thereof

wherein ring L, A, G and J have the meanings set forth for formula III.

In another aspect, the invention provides a compound of the formula V:

wherein A-G-J is R^(1a);

wherein R¹, R^(1a) and R^(2a) are each, independently, selected from thegroup consisting of H, substituted or unsubstituted alkyl, alkyl-aryl,heteroalkyl, heterocyclyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino,carboxyalkylamino, arlylalkyloxy and heterocyclylamino; all of which maybe further independently substituted one or more times with Z¹ and Z²;wherein Z¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl,arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl, orheteroarylalkyl; wherein Z¹ can be independently substituted with one ormore of Z² moieties which can be the same or different and areindependently selected; wherein Z² is hydroxy, alkyl, aryl, alkoxy,aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,alkylureido, arylureido, halogen, cyano, keto, ester or nitro; whereineach of said alkyl, alkoxy, and aryl can be unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different and are independently selected from alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl,aryl, alkylaryl, arylalkyl, arylheteroaryl, heteroaryl,heterocyclylamino, alkylheteroaryl and heteroarylalkyl;

or R¹ and R^(1a) may together form a 3, 4, 5, 6 or 7-membered ring thatis aromatic or non-aromatic and may contain one or more heteroatoms,wherein the ring may be further substituted one or more times withsubstitutents that are the same or different.

In one embodiment of formula V, R^(2a) is OH.

In another embodiment of the compounds of the invention, R¹ is H or CH₃,and A-G-J together form H, or together form a functional group selectedfrom the group consisting of

In another embodiment of the compounds of the invention, R¹ is H, andA-G-J together form a functional group selected from the groupconsisting of

wherein R¹³ is selected from the group consisting of hydrogen,hydroxymethyl, and aminomethyl or from the group consisting of:

wherein n is an integer equal to or averaging 1-500, 1,000, 2,000,3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000.

In another embodiment of formulas I or III, the core pyridinefunctionality is of the following N-oxide formula:

In one embodiment of the compounds of the invention, when J is not F, Jis bonded to O or N. In another embodiment, when R^(b) is not F, R^(a)is —(R¹)₂.

Preferred embodiments of formulas I, II, III, IV and V (includingpharmaceutically acceptable salts thereof, as well as enantiomers,stereoisomers, rotamers, tautomers, diastereomers, atropisomers orracemates thereof, including N-pyridine-oxides thereof) are shown belowin Table A and Table B, and are also considered to be “compounds of theinvention.” The compounds of the invention are also referred to hereinas “antibiotics” and “EF-Tu inhibitors.”

In yet another aspect, the invention provides a compound of the formulaVI:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof;

wherein

R is selected from the group consisting of N(R¹)₂, N(R¹)-A-G-Q-J, and-(heteroaryl)-A-G-Q-J;

A is a bond or is selected from the group consisting of —C(O)—,—C(O)C(O)—, —C(O)O—, —C(O)N(R^(8a))—, —S(O)₂—, —S(O)—, —S(O)₂N(R^(8a))—,—S(O)N(R^(8a))—, —C(═NR⁸)N(R^(8a))—, —C(═NR⁸)N(R^(8a))C(O)—, —C(═NR⁸)—,—C═C—C(O)—, —C═C—C(O)O—, —C═C—C(O)N(R^(8a))—;

G is absent, selected from the group consisting of—[C(R^(a))(R^(b))]_(x)—,—[C(R^(a))(R^(b))]_(x)—C(R^(a))═C(R^(a))—[C(R^(a))(R^(b))]_(y)—,—[C(R^(a))(R^(b))]_(x)—O—[C(R^(a))(R^(b))]_(y)—, and—[C(R^(a))(R^(b))]_(x)—N(R^(8a))—[C(R^(a))(R^(b))]_(y)—, or is selectedfrom the group consisting of -(cycloalkyl)-, -(heterocycle)-, -(aryl)-,and -(heteroaryl)- each of which has 0-4 substituents;

Q is absent, selected from the group consisting of—C(O)—[C(R^(a))(R^(b))]_(x)—,—C(O)—[C(R^(a))(R^(b))]_(x)—C(R^(a))═C(R^(a))—[C(R^(a))(R^(b))]_(y)—,—C(O)—[C(R^(a))(R^(b))]_(x)—O—[C(R^(a))(R^(b))]_(y)—, and—C(O)—{N(R^(8a))—[C(R^(a))(R^(b))]_(y)}_(p)—, or is selected from thegroup consisting of -(cycloalkyl)-, -(heterocycle)-, -(aryl)-,-(heteroaryl)-, —C(O)-(cycloalkyl)-, —C(O)-(heterocycle)-,—C(O)-(aryl)-, and —C(O)-(heteroaryl)-, each of which has 0-4substituents;

J is selected from the group consisting of H, C₁₋₄alkyl, halogen,C₁₋₄alkoxy, hydroxy, amino, mono- and di-C₁₋₄alkylamino,triC₁₋₄alkylammonium, N(R^(8a))C(O)C₁₋₄alkyl, CO₂H, C(═O)N(R^(8a))₂,CH₂CO₂H, CH₂C(═O)N(R^(8a))₂, CO₂—C₁₋₄alkyl, C(O)C₁₋₄alkyl, P(O)(OH)₂,P(O)(O—C₁₋₄alkyl)₂, C₀₋₄alkylene-(cycloalkyl) andC₀₋₄alkylene-(heterocycle), which heterocycle may be substituted 0-4times;

R^(a) is selected from the group consisting of H, alkyl, F, CO₂H,CO₂-alkyl, —N(R¹)₂, —OR¹, —(CH₂)₀₋₄-J and —R^(4b);

R^(b) is selected from the group consisting of H, alkyl, and F;

p is 0, 1, 2, or 3;

x and y are each, independently selected at each occurrence fromintegers from 0-10;

R¹ is independently selected at each occurrence from —H, alkylsubstituted with J, and —R^(4b).

R² is hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₀₋₆alkyl,C₃₋₇cycloalkylC₀₋₄alkyl, arylC₀₋₄alkyl, or a residue of the formula:

R^(2a) is selected from the group consisting of H, C₁₋₆alkyl, OH,OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ and N(R^(8a))₂;

R^(2b) is H or C₁₋₆alkyl, or R^(2a) and R^(2b) taken in combination forman oxo or imino group;

R³ and R¹² are each, independently, selected from the group consistingof H, halogen, OR^(4b), -G-J, and N(R^(8a))₂;

R^(4a) is selected from the group consisting of H and alkyl;

R^(4b) is selected from the group consisting of alkyl and—(CH₂—CH₂—O—)_(n)—R⁹, wherein n is an integer of 1-500, 1,000, 2,000,3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000or is a mean of a plurality of integers having a value of 1-500, 1,000,2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or60,000;

R⁵ is selected from the group consisting of H, alkyl, and R^(4b);

R⁸ is selected from the group consisting of H, CN, NO₂, C₁₋₆alkyl,C₃₋₇cycloalkyl, and SO₂—C₁₋₆alkyl;

R^(8a) is absent, or selected from the group consisting of H, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₁₋₆alkyl substituted with J, and R^(4b), or two R^(8a)residues, taken in combination may form a saturated, unsaturated oraromatic ring having 3 to 7 ring atoms, which ring may be substituted0-4 times; and

R⁹ is selected from the group consisting of H, alkyl and CH₂CO₂H.

Certain compounds of Formula VI include those compounds in which R² is aresidue of the formula:

R^(2a) is selected from the group consisting of H, C₁₋₆alkyl, OH,OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ and N(R^(8a))₂; and

R^(2b) is H or C₁₋₆alkyl, or R^(2a) and R^(2b) taken in combination forman oxo or imino group.

Still other compounds of Formula VI include those compounds in whichR^(2b), R^(4b) and R⁵ are H, and R^(4a) is CH₃. Certain other compoundsof Formula VI include those compounds in which R^(2b), R^(4b) and R⁵ areH, R^(4a) is CH₃, and R¹² is CH₂—O—CH₃. Other compounds of Formula VIinclude compounds in which R^(2a) is OH or OAc and R^(2b) is H. Stillother compounds of Formula VI include those compounds in which A isC(O), C(O)O, or C(O)NH; G is C₄₋₇cycloalkyl; Q is absent; and J is CO₂Hor CO₂C₁₋₄alkyl.

Other compounds of Formula VI include those compounds in which R isN(R¹)-A-G-Q-J, R¹ is H and A-G-Q-J together form H, or together form afunctional group selected from the group consisting of

Yet other compounds of Formula VI include those compounds in which R isN(R¹)-A-G-Q-J, R¹ is H and A-G-Q-J together form a functional groupselected from the group consisting of

wherein R¹³ is selected from the group consisting of hydrogen,hydroxymethyl, and aminomethyl or from the group consisting of:

n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000,20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality ofintegers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000,10,000, 20,000, 30,000, 40,000, 50,000, or 60,000.

Certain preferred compounds of Formula VI include, but are not limitedto, compounds of Formula VII:

and pharmaceutically acceptable salts thereof.

In yet another aspect, compounds are provided according to Formula VIII:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof;

wherein

is a 4-7 membered heteroaryl ring having 0-2 additional ring heteroatomswhich is substituted with a -A-G-Q-J residue and 0-4 additionalsubstituents;

A is a bond or is selected from the group consisting of —C(O)—,—C(O)C(O)—, —C(O)O—, —C(O)N(R^(8a))—, —S(O)₂—, —S(O)—, —S(O)₂N(R^(8a))—,—S(O)N(R^(8a))—, —C(═NR⁸)N(R^(8a))—, —C(═NR⁸)N(R^(8a))C(O)—, —C(═NR⁸)—,—C═C—C(O)—, —C═C—C(O)O—, —C═C—C(O)N(R^(8a))—;

G is absent, selected from the group consisting of—[C(R^(a))(R^(b))]_(x)—,—[C(R^(a))(R^(b))]_(x)—C(R^(a))═C(R^(a))—[C(R^(a))(R^(b))]_(y)—,—[C(R^(a))(R^(b))]_(x)—O—[C(R^(a))(R^(b))]_(y)—, and—[C(R^(a))(R^(b))]_(x)—N(R^(8a))—[C(R^(a))(R^(b))]_(y)—, or is selectedfrom the group consisting of -(cycloalkyl)-, -(heterocycle)-, -(aryl)-,and -(heteroaryl)- each of which has 0-4 substituents;

Q is absent, selected from the group consisting of—C(O)—[C(R^(a))(R^(b))]_(x)—,—C(O)—[C(R^(a))(R^(b))]_(x)—C(R^(a))═C(R^(a))—[C(R^(a))(R^(b))]_(y)—,—C(O)—[C(R^(a))(R^(b))]_(x)—O—[C(R^(a))(R^(b))]_(y)—, and—C(O)—{N(R^(8a))—[C(R^(a))(R^(b))]_(y)}_(p)—, or is selected from thegroup consisting of -(cycloalkyl)-, -(heterocycle)-, -(aryl)-,-(heteroaryl)-, —C(O)-(cycloalkyl)-, —C(O)-(heterocycle)-,—C(O)-(aryl)-, and —C(O)-(heteroaryl)-, each of which has 0-4substituents;

J is selected from the group consisting of H, C₁₋₄alkyl, halogen,C₁₋₄alkoxy, hydroxy, amino, mono- and di-C₁₋₄alkylamino,triC₁₋₄alkylammonium, N(R^(8a))C(O)C₁₋₄alkyl, CO₂H, C(═O)N(R^(8a))₂,CH₂CO₂H, CH₂C(═O)N(R^(8a))₂, CO₂—C₁₋₄alkyl, C(O)C₁₋₄alkyl, P(O)(OH)₂,P(O)(O—C₁₋₄alkyl)₂, C₀₋₄alkylene-(cycloalkyl) andC₀₋₄alkylene-(heterocycle), which heterocycle may be substituted 0-4times;

R^(a) is selected from the group consisting of H, alkyl, F, CO₂H,CO₂-alkyl, —N(R¹)₂, —OR¹, —(CH₂)₀₋₄-J and —R^(4b);

R^(b) is selected from the group consisting of H, alkyl, and F;

p is 0, 1, 2, or 3;

x and y are each, independently selected at each occurrence fromintegers from 0-10;

R¹ is independently selected at each occurrence from —H, alkylsubstituted with J, and R^(4b).

R² is hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₀₋₆alkyl,C₃₋₇cycloalkylC₀₋₄-alkyl, arylC₀₋₄alkyl, or a residue of the formula:

R^(2a) is selected from the group consisting of H, C₁₋₆alkyl, OH,OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ and N(R^(8a))₂;

R^(2b) is H or C₁₋₆alkyl, or R^(2a) and R^(2b) taken in combination forman oxo or imino group;

R³ and R¹² are each, independently, selected from the group consistingof H, halogen, OR^(4b), -G-J, and N(R^(8a))₂;

R^(4a) is selected from the group consisting of H and alkyl;

R^(4b) is selected from the group consisting of alkyl and—(CH₂—CH₂—O—)_(n)—R⁹, wherein n is an integer of 1-500, 1,000, 2,000,3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000or is a mean of a plurality of integers having a value of 1-500, 1,000,2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or60,000;

R⁵ is selected from the group consisting of H, alkyl, and R^(4b);

R⁸ is selected from the group consisting of H, CN, NO₂, C₁₋₆alkyl,C₃₋₇cycloalkyl, and SO₂—C₁₋₆alkyl;

R^(8a) is absent, or selected from the group consisting of H, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₁₋₆alkyl substituted with J, and R^(4b), or two R^(8a)residues, taken in combination may form a saturated, unsaturated oraromatic ring having 3 to 7 ring atoms, which ring may be substituted0-4 times; and

R⁹ is selected from the group consisting of H, alkyl and CH₂CO₂H.

Certain compounds of Formula VI include those compounds in which R² is aresidue of the formula:

R^(2a) is selected from the group consisting of H, C₁₋₆alkyl, OH,OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ and N(R^(8a))₂; and

R^(2b) is H or C₁₋₆alkyl, or R^(2a) and R^(2b) taken in combination forman oxo or imino group.

Still other compounds of Formula VIII include those compounds in whichR^(2b), R^(4b) and R⁵ are H, and R^(4a) is CH₃. Certain other compoundsof Formula VIII include those compounds in which R^(2b), R^(4b) and R⁵are H, R^(4a) is CH₃, and R¹² is CH₂—O—CH₃. Other compounds of FormulaVIII include compounds in which R^(2a) is OH or OAc and R^(2b) is H.Still other compounds of Formula VIII include those compounds in which Ais C(O), C(O)O, or C(O)NH; G is C₄₋₇cycloalkyl; Q is absent; and J isCO₂H or CO₂C₁₋₄alkyl.

Still other compounds of Formula VIII include those compounds in whichthe

residue is an imidazolyl ring substituted with A-G-Q-J; and A-G-Q-Jtogether form H, or together form a functional group selected from thegroup consisting of

Still other compounds of Formula VIII include those compounds in whichthe

residue is an imidazolyl ring substituted with A-G-Q-J; and A-G-Q-Jtogether form a functional group selected from the group consisting of

wherein R¹³ is selected from the group consisting of hydrogen,hydroxymethyl, and aminomethyl or from the group consisting of:

n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000,20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality ofintegers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000,10,000, 20,000, 30,000, 40,000, 50,000, or 60,000.

TABLE A Com- pound Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

TABLE B

R^(1a) =

R¹³ =

n = 1-60,000

In certain embodiments, the compound of the present invention is furthercharacterized as a modulator of EF-Tu, including a prokaryotic EF-Tu,and especially including a bacterial EF-Tu. In a preferred embodiment,the compound of the invention is an EF-Tu inhibitor.

As used herein, the term “bacterial infection(s)” includes, but is notlimited to, bacterial infections that occur in mammals, fish and birdsas well as disorders related to bacterial infections that may be treatedor prevented by administering antibiotics such as the compounds of thepresent invention. In addition to treating infections caused bymulti-drug resistant strains of Staphyloccocus aureus, Streptococcuspneumoniae, Mycobacterium tuberculosis and Enterococci, the compounds ofthe present invention are useful in treating infections caused by otherbacteria including, but not limited to, Clostridium difficile,Propionibacterium acnes, Bacteroides fagiles, Neisseria gonorrhoeae,Branhamella catarrhalis, Haemophilus influenzae, E. coli, Pseudomonasaeruginosa, Proteus vulgaris, Klebsiella pneumonia, and Chlamydiatrachomatis.

Such bacterial infections and disorders related to such infectionsinclude, but are not limited to, the following: acne, rosacea, skininfection, pneumonia, otitis media, sinusitus, bronchitis, tonsillitis,and mastoiditis related to infection by Streptococcus pneumoniae,Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus,Peptostreptococcus spp. or Pseudomonas spp.; pharynigitis, rheumaticfever, and glomerulonephritis related to infection by Streptococcuspyogenes, Groups C and G streptococci, Clostridium diptheriae, orActinobacillus haemolyticum; respiratory tract infections related toinfection by Mycoplasma pneumoniae, Legionella pneumophila,Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydiapneumoniae; uncomplicated skin and soft tissue infections, abscesses andosteomyelitis, and puerperal fever related to infection byStaphylococcus aureus, coagulase-positive staphylococci (i.e., S.epidermidis, S. hemolyticus, etc.), S. pyogenes, S. agalactiae,Streptococcal groups C-F (minute-colony streptococci), viridansstreptococci, Corynebacterium spp., Clostridium spp., or Bartonellahenselae; uncomplicated acute urinary tract infections related toinfection by S. saprophyticus or Enterococcus spp.; urethritis andcervicitis; sexually transmitted diseases related to infection byChlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum,Ureaplasma urealyticum, or Nesseria gonorrheae; toxin diseases relatedto infection by S. aureus (food poisoning and Toxic shock syndrome), orGroups A, S, and C streptococci; ulcers related to infection byHelicobacter pylori; systemic febrile syndromes related to infection byBorrelia recurrentis; Lyme disease related to infection by Borreliaburgdorferi; conjunctivitis, keratitis, and dacrocystitis related toinfection by C. trachomatis, N. gonorrhoeae, S. aureus, S. pneumoniae,S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobacteriumavium complex (MAC) disease related to infection by Mycobacterium avium,or Mycobacterium intracellulare; gastroenteritis related to infection byCampylobacter jejuni; intestinal protozoa related to infection byCryptosporidium spp., odontogenic infection related to infection byviridans streptococci; persistent cough related to infection byBordetella pertussis; gas gangrene related to infection by Clostridiumperfringens or Bacteroides spp.; Skin infection by S. aureus,Propionibacterium acne; atherosclerosis related to infection byHelicobacter pylori or Chlamydia pneumoniae; or the like.

Further bacterial infections and disorders related to such infectionsthat may be treated or prevented in animals include, but are not limitedto, the following: bovine respiratory disease related to infection by P.haemolytica., P. multocida, Mycoplasma bovis, or Bordetella spp.; cowenteric disease related to infection by E. coli or protozoa (i.e.,coccidia, cryptosporidia, etc.), dairy cow mastitis related to infectionby S. aureus, S. uberis, S. agalactiae, S. dysgalactiae, Klebsiellaspp., Corynebacterium, or Enterococcus spp.; swine respiratory diseaserelated to infection by A. pleuropneumoniae., P. multocida, orMycoplasma spp.; swine enteric disease related to infection by E. coli,Lawsonia intracellularis, Salmonella spp., or Serpulina hyodyisinteriae;cow footrot related to infection by Fusobacterium spp.; cow metritisrelated to infection by E. coli; cow hairy warts related to infection byFusobacterium necrophorum or Bacteroides nodosus; cow pink-eye relatedto infection by Moraxella bovis, cow premature abortion related toinfection by protozoa (i.e., neosporium); urinary tract infection indogs and cats related to infection by E. coli; skin and soft tissueinfections in dogs and cats related to infection by S. epidermidis, S.intermedius, coagulase neg. Staphylococcus or P. multocida; dental ormouth infections in dogs and goats related to infection by Alcaligenesspp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacteriumspp., Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp.,Actinomyces spp., Erysipelothrix spp., Rhodococcus spp., Trypanosomaspp., Plasmodium spp., Babesia spp., Toxoplasma spp., Pneumocystis spp.,Leishmania spp., Trichomonas spp. or Prevotella spp. Other bacterialinfections and disorders related to such infections that may be treatedor prevented in accord with the method of the present invention arereferred to in J. P. Sanford at al., “The Sanford Guide To AntimicrobialTherapy,” 26th Edition, (Antimicrobial Therapy, Inc., 1996).

Further bacterial infections and disorders related to such infectionsthat may be treated or prevented in animals include, but are not limitedto, central nervous system infections, external ear infections,infections of the middle ear, such as acute otitis media, infections ofthe cranial sinuses, eye infections, infections of the oral cavity, suchas infections of the teeth, gums and mucosa, upper respiratory tractinfections, lower respiratory tract infections, genitourinaryinfections, gastrointestinal infections, gynecological infections,septicemia, bone and joint infections, skin and skin structureinfections, bacterial endocarditis, burns, antibacterial prophylaxis ofsurgery, antibacterial prophylaxis in immunosuppressed patients, such aspatients receiving cancer chemotherapy, or organ transplant patients andchronic diseases caused by infectious organisms, e.g., arteriosclerosis.

Bacterial protein synthesis requires EF-Tu chaperone proteins. EF-Tu isone of the most abundant proteins in bacteria, as well as one of themost highly conserved, and in a number of species the gene is duplicatedwith identical function. When bound to GTP, EF-Tu can form a complexwith most aminoacylated tRNAs, loading the tRNA onto the ribosome. Inone embodiment, the bacterial infection is associated with the activityof EF-Tu. Without being bound by theory, it is believed that thedisruption of EF-Tu protein activity by the compounds of the inventionwill interfere with protein synthesis and thus bacterial function and/orproliferation. Because EF-Tu is highly conserved across Gram-positiveand Gram-negative bacteria, the compounds of the present invention areuseful for treating infections of both classes of bacteria.

As used herein, the term “EF-Tu-associated state” or “EF-Tu-associateddisorder” include disorders and states (e.g., a disease state) that areassociated with the activity of EF-Tu. A non-limiting example of anEF-Tu associated disorder is a bacterial infection in a subject.

The present invention includes treatment of bacterial infections, aswell as EF-Tu-associated disorders, as described above, but theinvention is not intended to be limited to the manner by which thecompound performs its intended function of treatment of a disease. Thepresent invention includes treatment of diseases described herein in anymanner that allows treatment to occur, e.g., bacterial infection.

In certain embodiments, the invention provides a pharmaceuticalcomposition of any of the compounds of the present invention. In arelated embodiment, the invention provides a pharmaceutical compositionof any of the compounds of the present invention and a pharmaceuticallyacceptable carrier or excipient of any of these compounds. In certainembodiments, the invention includes the compounds as novel chemicalentities.

In one embodiment, the invention includes a packaged bacterial infectiontreatment. The packaged treatment includes a compound of the inventionpackaged with instructions for using an effective amount of the compoundof the invention for an intended use.

The compounds of the present invention are suitable as active agents inpharmaceutical compositions that are efficacious particularly fortreating bacterial infections. The pharmaceutical composition in variousembodiments has a pharmaceutically effective amount of the presentactive agent along with other pharmaceutically acceptable excipients,carriers, fillers, diluents and the like. The phrase, “pharmaceuticallyeffective amount” as used herein indicates an amount necessary toadminister to a host, or to a cell, issue, or organ of a host, toachieve a therapeutic result, especially an anti-bacterial infectioneffect, e.g., inhibition of proliferation of a bacterium, or of anyother bacterial infection.

In other embodiments, the present invention provides a method forinhibiting the activity of an EF-Tu protein. The method includescontacting a cell with any of the compounds of the present invention. Ina related embodiment, the method further provides that the compound ispresent in an amount effective to selectively inhibit the activity of anEF-Tu protein.

In other embodiments, the present invention provides a use of any of thecompounds of the invention for manufacture of a medicament to treat abacterial infection in a subject.

In other embodiments, the invention provides a method of manufacture ofa medicament, including formulating any of the compounds of the presentinvention for treatment of a subject.

DEFINITIONS

The term “treat,” “treated,” “treating” or “treatment” includes thediminishment or alleviation of at least one symptom associated or causedby the state, disorder or disease being treated. In certain embodiments,the treatment comprises the induction of a bacterial infection, followedby the activation of the compound of the invention, which would in turndiminish or alleviate at least one symptom associated or caused by thebacterial infection being treated. For example, treatment can bediminishment of one or several symptoms of a disorder or completeeradication of a disorder.

The term “subject” is intended to include organisms, e.g., prokaryotesand eukaryotes, which are capable of suffering from or afflicted with abacterial infection. Examples of subjects include mammals, e.g., humans,dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, andtransgenic non-human animals. In certain embodiments, the subject is ahuman, e.g., a human suffering from, at risk of suffering from, orpotentially capable of suffering from a bacterial infection, and fordiseases or conditions described herein. In another embodiment, thesubject is a cell.

The language “EF-Tu-modulating compound,” “modulator of EF-Tu” or “EF-Tuinhibitor” refers to compounds that modulate, e.g., inhibit, orotherwise alter, the activity of EF-Tu. Examples of EF-Tu-modulatingcompounds include compounds of formula I, II, III, IV and V, as well asTable A and Table B (including pharmaceutically acceptable saltsthereof, as well as enantiomers, stereoisomers, rotamers, tautomers,diastereomers, atropisomers or racemates thereof).

Additionally, a method of the invention includes administering to asubject an effective amount of an EF-Tu-modulating compound of theinvention, e.g., EF-Tu-modulating compounds of Formula I, II, III, IVand V, as well as Table A and Table B (including pharmaceuticallyacceptable salts thereof, as well as enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof).

The term “alkyl” includes saturated aliphatic groups, includingstraight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups(isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups(cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkylsubstituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.The term “alkyl” also includes alkenyl groups and alkynyl groups.Furthermore, the expression “C_(x)-C_(y)-alkyl”, wherein x is 1-5 and yis 2-10 indicates a particular alkyl group (straight- or branched-chain)of a particular range of carbons. For example, the expressionC₁-C₄-alkyl includes, but is not limited to, methyl, ethyl, propyl,butyl, isopropyl, tert-butyl, isobutyl and sec-butyl. Moreover, the termC₃₋₆-cycloalkyl includes, but is not limited to, cyclopropyl,cyclopentyl, and cyclohexyl. As discussed below, these alkyl groups, aswell as cycloalkyl groups, may be further substituted. “C₀-C_(n)alkyl”refers to a single covalent bond (C₀) or an alkyl group having from 1 ton carbon atoms; for example “C₀-C₄alkyl” refers to a single covalentbond or a C₁-C₄alkyl group; “C₀-C₈alkyl” refers to a single covalentbond or a C₁-C₈alkyl group. In some instances, a substituent of an alkylgroup is specifically indicated. For example, “C₁-C₄hydroxyalkyl” refersto a C₁-C₄alkyl group that has at least one hydroxy substituent.

“Alkylene” refers to a divalent alkyl group, as defined above.C₀-C₄alkylene is a single covalent bond or an alkylene group having from1 to 4 carbon atoms; and C₀-C₆alkylene is a single covalent bond or analkylene group having from 1 to 6 carbon atoms. “Alkenylene” and“Alkynylene” refer to divalent alkenyl and alkynyl groups respectively,as defined above.

A “cycloalkyl” is a group that comprises one or more saturated and/orpartially saturated rings in which all ring members are carbon, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, andpartially saturated variants of the foregoing, such as cyclohexenyl.Cycloalkyl groups do not comprise an aromatic ring or a heterocyclicring. Certain cycloalkyl groups are C₃-C₈cycloalkyl, in which the groupcontains a single ring with from 3 to 8 ring members. A“(C₃-C₈cycloalkyl)C₀-C₄alkyl” is a C₃-C₈cycloalkyl group linked via asingle covalent bond or a C₁-C₄alkylene group. In certain aspects,C₃₋₆-cycloalkyl groups are substituted one or more times (or preferablybetween one and five times) with substitutents independently selectedfrom a halogen atom, aryl, heteroaryl, trihalomethyl, C₁₋₄-alkoxy orC₁₋₄-alkyl.

Moreover, alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl,etc.) include both “unsubstituted alkyl” and “substituted alkyl”, thelatter of which refers to alkyl moieties having substituents replacing ahydrogen on one or more carbons of the hydrocarbon backbone, which allowthe molecule to perform its intended function.

The term “substituted” is intended to describe moieties havingsubstituents replacing a hydrogen on one or more atoms, e.g. C, O or N,of a molecule. Such substituents can include, for example, oxo, alkyl,alkoxy, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, morpholino,phenol, benzyl, phenyl, piperizine, cyclopentane, cyclohexane, pyridine,5H-tetrazole, triazole, piperidine, or an aromatic or heteroaromaticmoiety, and any combination thereof.

Further examples of substituents of the invention, which are notintended to be limiting, include moieties selected from straight orbranched alkyl (preferably C₁-C₅), cycloalkyl (preferably C₃-C₈), alkoxy(preferably C₁-C₆), thioalkyl (preferably C₁-C₆), alkenyl (preferablyC₂-C₆), alkynyl (preferably C₂-C₆), heterocyclic, carbocyclic, aryl(e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl),aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl,heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group,heteroarylcarbonyl, or heteroaryl group, (CR′R″)₀₋₃NR′R″ (e.g., —NH₂),(CR′R″)₀₋₃CN (e.g., —CN), —NO₂, halogen (e.g., —F, —Cl, —Br, or —I),(CR′R″)₀₋₃C(halogen)₃ (e.g., —CF₃), (CR′R″)₀₋₃CH(halogen)₂,(CR′R″)₀₋₃CH₂(halogen), (CR′R″)₀₋₃CONR′R″, (CR′R″)₀₋₃(CNH)NR′R″,(CR′R″)₀₋₃S(O)₁₋₂NR′R″, (CR′R″)₀₋₃CHO, (CR′R″)₀₋₃O(CR′R″)₀₋₃H,(CR′R″)₀₋₃S(O)₀₋₃R′ (e.g., —SO₃H, —OSO₃H), (CR′R″)₀₋₃O(CR′R″)₀₋₃H (e.g.,—CH₂OCH₃ and —OCH₃), (CR′R″)₀₋₃S(CR′R″)₀₋₃H (e.g., —SH and —SCH₃),(CR′R″)₀₋₃OH (e.g., —OH), (CR′R″)₀₋₃COR′, (CR′R″)₀₋₃(substituted orunsubstituted phenyl), (CR′R″)₀₋₃(C₃-C₈ cycloalkyl), (CR′R″)₀₋₃CO₂R′(e.g., —CO₂H), or (CR′R″)₀₋₃OR′ group, or the side chain of anynaturally occurring amino acid; wherein R′ and R″ are each independentlyhydrogen, a C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, or aryl group.Such substituents can include, for example, halogen, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,phosphinato, cyano, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, oxime, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl,cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety, andany combination thereof. In certain embodiments, a carbonyl moiety (C═O)may be further derivatized with an oxime moiety, e.g., an aldehydemoiety may be derivatized as its oxime (—C═N—OH) analog. It will beunderstood by those skilled in the art that the moieties substituted onthe hydrocarbon chain can themselves be substituted, if appropriate.Cycloalkyls can be further substituted, e.g., with the substituentsdescribed above. An “aralkyl” moiety is an alkyl substituted with anaryl (e.g., phenylmethyl (i.e., benzyl)).

The term “alkenyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one double bond.

For example, the term “alkenyl” includes straight-chain alkenyl groups(e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl(alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenylgroups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. Theterm alkenyl further includes alkenyl groups that include oxygen,nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone. In certain embodiments, a straight chain orbranched chain alkenyl group has 6 or fewer carbon atoms in its backbone(e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). Likewise,cycloalkenyl groups may have from 3-8 carbon atoms in their ringstructure, and more preferably have 5 or 6 carbons in the ringstructure. The term C₂-C₆ includes alkenyl groups containing 2 to 6carbon atoms.

Moreover, the term alkenyl includes both “unsubstituted alkenyls” and“substituted alkenyls”, the latter of which refers to alkenyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “alkynyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one triple bond.

For example, the term “alkynyl” includes straight-chain alkynyl groups(e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkylor cycloalkenyl substituted alkynyl groups. The term alkynyl furtherincludes alkynyl groups that include oxygen, nitrogen, sulfur orphosphorous atoms replacing one or more carbons of the hydrocarbonbackbone. In certain embodiments, a straight chain or branched chainalkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆ for branched chain). The term C₂-C₆ includesalkynyl groups containing 2 to 6 carbon atoms.

Moreover, the term alkynyl includes both “unsubstituted alkynyls” and“substituted alkynyls”, the latter of which refers to alkynyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “amine” or “amino” should be understood as being broadlyapplied to both a molecule, or a moiety or functional group, asgenerally understood in the art, and may be primary, secondary, ortertiary. The term “amine” or “amino” includes compounds where anitrogen atom is covalently bonded to at least one carbon, hydrogen orheteroatom. The terms include, for example, but are not limited to,“alkylamino,” “arylamino,” “diarylamino,” “alkylarylamino,”“alkylaminoaryl,” “arylaminoalkyl,” “alkaminoalkyl,” “amide,” “amido,”and “aminocarbonyl.” The term “alkyl amino” comprises groups andcompounds wherein the nitrogen is bound to at least one additional alkylgroup. The term “dialkyl amino” includes groups wherein the nitrogenatom is bound to at least two additional alkyl groups. The term“arylamino” and “diarylamino” include groups wherein the nitrogen isbound to at least one or two aryl groups, respectively. The term“alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to anamino group which is bound to at least one alkyl group and at least onearyl group. The term “alkaminoalkyl” refers to an alkyl, alkenyl, oralkynyl group bound to a nitrogen atom which is also bound to an alkylgroup.

The term “amide,” “amido” or “aminocarbonyl” includes compounds ormoieties which contain a nitrogen atom which is bound to the carbon of acarbonyl or a thiocarbonyl group. The term includes “alkaminocarbonyl”or “alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl oralkynyl groups bound to an amino group bound to a carbonyl group. Itincludes arylaminocarbonyl and arylcarbonylamino groups which includearyl or heteroaryl moieties bound to an amino group which is bound tothe carbon of a carbonyl or thiocarbonyl group. The terms“alkylaminocarbonyl,” “alkenylaminocarbonyl,” “alkynylaminocarbonyl,”“arylaminocarbonyl,” “alkylcarbonylamino,” “alkenylcarbonylamino,”“alkynylcarbonylamino,” and “arylcarbonylamino” are included in term“amide.” Amides also include urea groups (aminocarbonylamino) andcarbamates (oxycarbonylamino).

The term “aryl” includes groups, including 5- and 6-membered single-ringaromatic groups that may include from zero to four heteroatoms, forexample, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole,imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine,pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, theterm “aryl” includes multicyclic aryl groups, e.g., tricyclic, bicyclic,e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole,benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline,isoquinoline, anthryl, phenanthryl, napthridine, indole, benzofuran,purine, benzofuran, deazapurine, or indolizine. Those aryl groups havingheteroatoms in the ring structure may also be referred to as “arylheterocycles”, “heterocycles,” “heteroaryls” or “heteroaromatics.” Thearomatic ring can be substituted at one or more ring positions with suchsubstituents as described above, as for example, alkyl, halogen,hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino(including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Arylgroups can also be fused or bridged with alicyclic or heterocyclic ringswhich are not aromatic so as to form a polycycle (e.g., tetralin).

The term heteroaryl, as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 5- to 10-membered aromatic or nonaromatic heterocycle containingfrom 1 to 4 heteroatoms selected from the group consisting of O, N andS, and includes bicyclic groups. “Heterocyclyl” therefore includes theabove mentioned heteroaryls, as well as dihydro and tetrahydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

The term “acyl” includes compounds and moieties which contain the acylradical (CH₃CO—) or a carbonyl group. The term “substituted acyl”includes acyl groups where one or more of the hydrogen atoms arereplaced by for example, alkyl groups, alkynyl groups, halogens,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The term “acylamino” includes moieties wherein an acyl moiety is bondedto an amino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

The term “alkoxy” includes substituted and unsubstituted alkyl, alkenyl,and alkynyl groups covalently linked to an oxygen atom. Examples ofalkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy,and pentoxy groups and may include cyclic groups such as cyclopentoxy.Examples of substituted alkoxy groups include halogenated alkoxy groups.The alkoxy groups can be substituted with groups such as alkenyl,alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moieties. Examples of halogen substituted alkoxygroups include, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc.

The term “carbonyl” or “carboxy” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom, andtautomeric forms thereof. Examples of moieties that contain a carbonylinclude aldehydes, ketones, carboxylic acids, amides, esters,anhydrides, etc. The term “carboxy moiety” or “carbonyl moiety” refersto groups such as “alkylcarbonyl” groups wherein an alkyl group iscovalently bound to a carbonyl group, “alkenylcarbonyl” groups whereinan alkenyl group is covalently bound to a carbonyl group,“alkynylcarbonyl” groups wherein an alkynyl group is covalently bound toa carbonyl group, “arylcarbonyl” groups wherein an aryl group iscovalently attached to the carbonyl group. Furthermore, the term alsorefers to groups wherein one or more heteroatoms are covalently bondedto the carbonyl moiety. For example, the term includes moieties such as,for example, aminocarbonyl moieties, (wherein a nitrogen atom is boundto the carbon of the carbonyl group, e.g., an amide), aminocarbonyloxymoieties, wherein an oxygen and a nitrogen atom are both bond to thecarbon of the carbonyl group (e.g., also referred to as a “carbamate”).Furthermore, aminocarbonylamino groups (e.g., ureas) are also include aswell as other combinations of carbonyl groups bound to heteroatoms(e.g., nitrogen, oxygen, sulfur, etc. as well as carbon atoms).Furthermore, the heteroatom can be further substituted with one or morealkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. moieties.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to a sulfur atom.The term “thiocarbonyl moiety” includes moieties that are analogous tocarbonyl moieties. For example, “thiocarbonyl” moieties includeaminothiocarbonyl, wherein an amino group is bound to the carbon atom ofthe thiocarbonyl group, furthermore other thiocarbonyl moieties include,oxythiocarbonyls (oxygen bound to the carbon atom),aminothiocarbonylamino groups, etc.

The term “ether” includes compounds or moieties that contain an oxygenbonded to two different carbon atoms or heteroatoms. For example, theterm includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom that is covalentlybonded to another alkyl group.

The term “ester” includes compounds and moieties that contain a carbonor a heteroatom bound to an oxygen atom that is bonded to the carbon ofa carbonyl group. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are asdefined above.

The term “thioether” includes compounds and moieties which contain asulfur atom bonded to two different carbon or hetero atoms. Examples ofthioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom that is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” and alkthioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomwhich is covalently bonded to an alkynyl group.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

The terms “polycyclyl” or “polycyclic radical” include moieties with twoor more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocyclyls) in which two or more carbons are common to twoadjoining rings, e.g., the rings are “fused rings”. Rings that arejoined through non-adjacent atoms are termed “bridged” rings. Each ofthe rings of the polycycle can be substituted with such substituents asdescribed above, as for example, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl,alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (includingalkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “heteroatom” includes atoms of any element other than carbon orhydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur andphosphorus.

Additionally, the phrase “any combination thereof” implies that anynumber of the listed functional groups and molecules may be combined tocreate a larger molecular architecture. For example, the terms “phenyl,”“carbonyl” (or “═O”), “—O—,” “—OH,” and C₁₋₆ (i.e., —CH₃ and—CH₂CH₂CH₂—) can be combined to form a 3-methoxy-4-propoxybenzoic acidsubstituent. It is to be understood that when combining functionalgroups and molecules to create a larger molecular architecture,hydrogens can be removed or added, as required to satisfy the valence ofeach atom.

It is to be understood that all of the compounds of the inventiondescribed above will further include bonds between adjacent atoms and/orhydrogens as required to satisfy the valence of each atom. That is,bonds and/or hydrogen atoms are added to provide the following number oftotal bonds to each of the following types of atoms: carbon: four bonds;nitrogen: three bonds; oxygen: two bonds; and sulfur: two-six bonds.

It will be noted that the structures of some of the compounds of thisinvention include asymmetric carbon atoms. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers, stereoisomers, rotamers, tautomers, diastereomers, orracemates) are included within the scope of this invention. Such isomerscan be obtained in substantially pure form by classical separationtechniques and by stereochemically controlled synthesis. Furthermore,the structures and other compounds and moieties discussed in thisapplication also include all tautomers thereof. Compounds describedherein may be obtained through art recognized synthesis strategies.

It will also be noted that the substituents of some of the compounds ofthis invention include isomeric cyclic structures. It is to beunderstood accordingly that constitutional isomers of particularsubstituents are included within the scope of this invention, unlessindicated otherwise. For example, the term “tetrazole” includestetrazole, 2H-tetrazole, 3H-tetrazole, 4H-tetrazole and 5H-tetrazole.

Use in Bacterial Infection

The compounds of the present invention have valuable pharmacologicalproperties and are useful in the treatment of diseases. In certainembodiments, compounds of the invention are useful in the treatment ofbacterial infections.

The term “use” includes any one or more of the following embodiments ofthe invention, respectively: the use in the treatment of bacterialinfections; the use for the manufacture of pharmaceutical compositionsfor use in the treatment of these diseases, e.g., in the manufacture ofa medicament; methods of use of compounds of the invention in thetreatment of these diseases; pharmaceutical preparations havingcompounds of the invention for the treatment of these diseases; andcompounds of the invention for use in the treatment of these diseases;as appropriate and expedient, if not stated otherwise. In particular,diseases to be treated and are thus preferred for use of a compound ofthe present invention are selected from bacterial infections, as well asthose diseases that depend on the activity of EF-Tu. The term “use”further includes embodiments of compositions herein which bind to anEF-Tu protein sufficiently to serve as tracers or labels, so that whencoupled to a fluor or tag, or made radioactive, can be used as aresearch reagent or as a diagnostic or an imaging agent.

In certain embodiments, a compound of the present invention is used fortreating EF-Tu-associated diseases, and use of the compound of thepresent invention as an inhibitor of any one or more EF-Tu proteins. Itis envisioned that a use can be a treatment of inhibiting one or moreisoforms of EF-Tu.

Assays

The inhibition of antibacterial activity by the compounds of theinvention may be measured using a number of assays available in the art.An example of such an assay is the standard minimum inhibitoryconcentration (MIC) test conducted according to CSLI guidelines.

Pharmaceutical Compositions

The language “effective amount” of the compound is that amount necessaryor sufficient to treat or prevent a bacterial infection, e.g. preventthe various morphological and somatic symptoms of a bacterial infection,and/or a disease or condition described herein. In an example, aneffective amount of the compound of the invention is the amountsufficient to treat a bacterial infection in a subject. The effectiveamount can vary depending on such factors as the size and weight of thesubject, the type of illness, or the particular compound of theinvention. For example, the choice of the compound of the invention canaffect what constitutes an “effective amount.” One of ordinary skill inthe art would be able to study the factors contained herein and make thedetermination regarding the effective amount of the compounds of theinvention without undue experimentation.

The regimen of administration can affect what constitutes an effectiveamount. The compound of the invention can be administered to the subjecteither prior to or after the onset of a bacterial infection. Further,several divided dosages, as well as staggered dosages, can beadministered daily or sequentially, or the dose can be continuouslyinfused, or can be a bolus injection. Further, the dosages of thecompound(s) of the invention can be proportionally increased ordecreased as indicated by the exigencies of the therapeutic orprophylactic situation.

Compounds of the invention may be used in the treatment of states,disorders or diseases as described herein, or for the manufacture ofpharmaceutical compositions for use in the treatment of these diseases.Methods of use of compounds of the present invention in the treatment ofthese diseases, or pharmaceutical preparations having compounds of thepresent invention for the treatment of these diseases.

The language “pharmaceutical composition” includes preparations suitablefor administration to mammals, e.g., humans. When the compounds of thepresent invention are administered as pharmaceuticals to mammals, e.g.,humans, they can be given per se or as a pharmaceutical compositioncontaining, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) ofactive ingredient in combination with a pharmaceutically acceptablecarrier.

The phrase “pharmaceutically acceptable carrier” is art recognized andincludes a pharmaceutically acceptable material, composition or vehicle,suitable for administering compounds of the present invention tomammals. The carriers include liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting the subject agent from one organ, or portion of the body,to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not injurious to the patient. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, α-tocopherol, and the like; and metal chelating agents, such ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaricacid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteraladministration. The formulations may conveniently be presented in unitdosage form and may be prepared by any methods well known in the art ofpharmacy. The amount of active ingredient that can be combined with acarrier material to produce a single dosage form will generally be thatamount of the compound that produces a therapeutic effect. Generally,out of one hundred percent, this amount will range from about 1 percentto about ninety-nine percent of active ingredient, preferably from about5 percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,cetyl alcohol and glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions that can be used include polymeric substances andwaxes. The active ingredient can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluent commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activecompound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given by formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc., administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral and/or IV administration is preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above. Generally, intravenous and subcutaneousdoses of the compounds of this invention for a patient, when used forthe indicated analgesic effects, will range from about 0.0001 to about100 mg per kilogram of body weight per day, more preferably from about0.01 to about 50 mg per kg per day, and still more preferably from about1.0 to about 100 mg per kg per day. An effective amount is that amounttreats a bacterial infection.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical composition.

Synthetic Procedure

Compounds of the present invention are prepared from commonly availablecompounds using procedures known to those skilled in the art, includingany one or more of the following conditions without limitation:

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group,” unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such ase.g., Science of Synthesis: Houben-Weyl Methods of MolecularTransformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp.(URL: http://www.science-of-synthesis.com (Electronic Version, 48Volumes)); J. F. W. McOmie, “Protective Groups in Organic Chemistry”,Plenum Press, London and New York 1973, in T. W. Greene and P. G. M.Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley,New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J.Meienhofer), Academic Press, London and New York 1981, in “Methoden derorganischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4thedition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D.Jakubke and H. Jeschkeit, “Aminosäuren, Peptide, Proteine” (Amino acids,Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharideand Derivate” (Chemistry of Carbohydrates: Monosaccharides andDerivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic ofprotecting groups is that they can be removed readily (i.e., without theoccurrence of undesired secondary reactions) for example by solvolysis,reduction, photolysis or alternatively under physiological conditions(e.g., by enzymatic cleavage).

Salts of compounds of the present invention having at least onesalt-forming group may be prepared in a manner known per se. Forexample, salts of compounds of the present invention having acid groupsmay be formed, for example, by treating the compounds with metalcompounds, such as alkali metal salts of suitable organic carboxylicacids, e.g., the sodium salt of 2-ethylhexanoic acid, with organicalkali metal or alkaline earth metal compounds, such as thecorresponding hydroxides, carbonates or hydrogen carbonates, such assodium or potassium hydroxide, carbonate or hydrogen carbonate, withcorresponding calcium compounds or with ammonia or a suitable organicamine, stoichiometric amounts or only a small excess of the salt-formingagent preferably being used. Acid addition salts of compounds of thepresent invention are obtained in customary manner, e.g., by treatingthe compounds with an acid or a suitable anion exchange reagent.Internal salts of compounds of the present invention containing acid andbasic salt-forming groups, e.g., a free carboxy group and a free aminogroup, may be formed, e.g., by the neutralisation of salts, such as acidaddition salts, to the isoelectric point, e.g., with weak bases, or bytreatment with ion exchangers.

Salts can be converted in customary manner into the free compounds;metal and ammonium salts can be converted, for example, by treatmentwith suitable acids, and acid addition salts, for example, by treatmentwith a suitable basic agent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known per se into the individual isomers;diastereoisomers can be separated, for example, by partitioning betweenpolyphasic solvent mixtures, recrystallisation and/or chromatographicseparation, for example over silica gel or by, e.g., medium pressureliquid chromatography over a reversed phase column, and racemates can beseparated, for example, by the formation of salts with optically puresalt-forming reagents and separation of the mixture of diastereoisomersso obtainable, for example by means of fractional crystallisation, or bychromatography over optically active column materials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g., using chromatographic methods,distribution methods, (re-) crystallization, and the like.

General Process Conditions

The following applies in general to all processes mentioned throughoutthis disclosure.

The process steps to synthesize the compounds of the invention can becarried out under reaction conditions that are known per se, includingthose mentioned specifically, in the absence or, customarily, in thepresence of solvents or diluents, including, for example, solvents ordiluents that are inert towards the reagents used and dissolve them, inthe absence or presence of catalysts, condensation or neutralizingagents, for example ion exchangers, such as cation exchangers, e.g., inthe H⁺ form, depending on the nature of the reaction and/or of thereactants at reduced, normal or elevated temperature, for example in atemperature range of from about −100° C. to about 190° C., including,for example, from approximately −80° C. to approximately 150° C., forexample at from −80 to −60° C., at room temperature, at from −20 to 40°C. or at reflux temperature, under atmospheric pressure or in a closedvessel, where appropriate under pressure, and/or in an inert atmosphere,for example under an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers, for example analogously tothe methods described in Science of Synthesis: Houben-Weyl Methods ofMolecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofurane ordioxane, liquid aromatic hydrocarbons, such as benzene or toluene,alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, suchas acetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, or mixtures of those solvents, for example aqueoussolutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

Prodrugs

This invention also encompasses pharmaceutical compositions containing,and methods of treating bacterial infections through administering,pharmaceutically acceptable prodrugs of compounds of the compounds ofthe invention. For example, compounds of the invention having freeamino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of compounds of the invention.The amino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols andalso includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

Any reference to a compound of the present invention is therefore to beunderstood as referring also to the corresponding pro-drugs of thecompound of the present invention, as appropriate and expedient.

Combinations

A compound of the present invention may also be used in combination withother agents, e.g., an additional antibacterial compound that is or isnot a compound of the invention, for treatment of a bacterial infectionin a subject.

By the term “combination” is meant either a fixed combination in onedosage unit form, or a kit of parts for the combined administrationwhere a compound of the present invention and a combination partner maybe administered independently at the same time or separately within timeintervals that especially allow that the combination partners show acooperative, e.g., synergistic, effect, or any combination thereof

A compound of the present invention may be used in combination withanother antibacterial agent. The term “antibacterial agent” refers toany substance that is either bactericidal or bacteriostatic, i.e.,capable of killing or inhibiting the growth of bacterial cells.Antibacterial agents include antibiotics, biocides, antimicrobials, andbacteriostatic agents. The known types of antibiotics include, e.g.,cell wall synthesis inhibitors, cell membrane inhibitors, proteinsynthesis inhibitors and inhibitors that bind to or affect the synthesisof DNA or RNA. Numerous antibiotic agents suitable for use in thetreatment of bacteria-related diseases and disorders, are known anddisclosed, e.g. in The Physician's Desk Reference (PDR), MedicalEconomics Company (Montvale, N.J.), (53.sup.rd Ed.), 1999; Mayo MedicalCenter Formulary, Unabridged Version, Mayo Clinic (Rochester, Minn.),January 1998; Merck Index: An Encyclopedia of Chemicals, Drugs andBiologicals, (11.sup.th Ed.), Merck & Co., Inc. (Rahway, N.J.), 1989;University of Wisconsin Antimicrobial Use Guide,http://www.medsch.wisc.edu/clinsci/5amcg/amcg.html; Introduction on theUse of the Antibiotics Guideline, of Specific Antibiotic Classes, ThomasJefferson University,http://jeffiine.tju.edu/CWIS/OAC/antibiotics_guide/intro.html; andreferences cited therein.

Examples of antibiotics for use in combination with the compounds of theinvention include, but are not limited to, quinolone, macrolide,glycopeptide, oxazolidinone, β-lactams (including amoxicillin,ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin,flucloxacillin, methicillin, mezlocillin, nafcillin, oxacillin,penicillin G, penicillin V, piperacillin, pivampicillin, pivmecillinam,ticarcillin, sulbactam, tazobactam, clavulanate), cephalosporins(cefaclor, cefadroxil, cefamandole, cefazolin, cefdinir, cefditoren,cefepime, cefixime, cefonicid, cefoperazone, cefotaxime, cefotetan,cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefuroxime, cephalexin, cephalothin, cephapirin,cephradine), aminoglycosides (including gentamycin, streptomycin,amikacin, kanamycin, viomycin, capreomycin), ethionamide, prothionamide,cycloserine, dapsone, clofazimine, tetracyclines (tetracycline,doxycycline, chlortetracycline, oxytetracycline, minocyclinedemeclocycline), oxazolidinones (linezolid, eperezolid), metronidazole,rifabutin, isoniazonid, ethambutol, and combinations thereof.

Examples of anti-viral agents for use in combination with the compoundsof the invention include, but are not limited to, zidovudine,lamivudine, didanosine, zalcitabine, stavudine, abacavir, nevirapine,delavirdine, emtricitabine, efavirenz, saquinavir, ritonavir, indinavir,nelfinavir, amprenavir, tenofovir, adefovir, atazanavir, fosamprenavir,hydroxyurea, AL-721, ampligen, butylated hydroxytoluene;polymannoacetate, castanospermine; contracan; creme pharmatex, CS-87,penciclovir, famciclovir, acyclovir, cytofovir, ganciclovir, dextransulfate, D-penicillamine trisodium phosphonoformate, fusidic acid,HPA-23, eflornithine, nonoxynol, pentamidine isethionate, peptide T,phenyloin, isoniazid, ribavirin, rifabutin, ansamycin, trimetrexate,SK-818, suramin, UA001, enfuvirtide, gp41-derived peptides, antibodiesto CD4, soluble CD4, CD4-containing molecules, CD4-IgG2, andcombinations thereof.

Further examples of agents the compounds of the present invention can beused in combination with include, but are not limited to, free radicalscavengers, ascorbic acid, Vitamin C, anti-cancer agents,chemotherapeutic agents, non-steroidal anti-inflammatory drugs,steroidal anti-inflammatory drugs, anti-fungal agents, detoxifyingagents, analgesics, bronchodilators, drugs for the treatment of vascularischemia anti-body monoclonal agent, minoxidil for topical applicationfor hair growth, diuretics, immunosuppressants, lymphokynes,α-and-β-interferon and combinations thereof.

The compound of the invention and any additional agent may be formulatedin separate dosage forms. Alternatively, to decrease the number ofdosage forms administered to a patient, the compound of the inventionand any additional agent may be formulated together in any combination.For example, the compound of the invention inhibitor may be formulatedin one dosage form and the additional agent may be formulated togetherin another dosage form. Any separate dosage forms may be administered atthe same time or different times.

Alternatively, a composition of this invention comprises an additionalagent as described herein. Each component may be present in individualcompositions, combination compositions, or in a single composition.

Exemplification of the Invention

The invention is further illustrated by the following examples, whichshould not be construed as further limiting. The practice of the presentinvention will employ, unless otherwise indicated, conventionaltechniques of cell biology, cell culture, molecular biology, transgenicbiology, microbiology and immunology, which are within the skill of theart.

General Synthesis Methods

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

EXAMPLES

Definitions AcOH acetic acid aq aqueous Boc tert-butoxycarbonyl DMFN,N-dimethylformamide DCC N,N-dicyclohexylcarbodiimide DCEdichloroethane DCM dichloromethane DMAP 4-dimethylaminopyridine DMSOdimethylsulfoxide EtOAc ethyl acetate EtOH ethanol eq equivalents LCliquid chromatography LCMS liquid chromatography mass spectrum MeOHmethanol MHz megahertz PS polystyrene RT room temperature R_(t)retention time s solid sat. saturated TEA triethylamine TFAtrifluoroacetic acid THF tetrahydrofuran h hours min minutes m/z mass tocharge MS mass spectrum HRMS high resolution mass spectrum NMR nuclearmagnetic resonance

Analytical Methods

NMR: proton spectra are recorded on a Bruker 400 MHz ultrashieldspectrometer. Chemical shifts are reported relative to methanol (δ3.31), dimethyl sulfoxide (δ 2.50), or chloroform (δ 7.26).

LCMS: compounds are analyzed on an Inertsil ODS-3 column (C18, 50×4.6mm, 3 μm) with a 2 min gradient elution (25% acetonitrile/H₂O/5 mMammonium formate) and a flow rate of 4 ml/min.

HPLC purification utilizes a C8 or C18 column (30×100 mm, 5 μm, brand:Sunfire or XTerra) and is performed according to two methods. Method 1consists of 0.1% TFA in 10%-95% ACN in H₂O. Method 2 consists of 10 mMNH₄OH in 40%-95% ACN in H₂O.

LC analysis utilizes an Atlantis brand C18 column (150 mm) with gradientelution (0-95% acetonitrile in water+0.1% TFA).

The compound of general formula (I) may be prepared via syntheticmethods well known to those skilled in the art, or alternativelyisolated from a fermentation broth. See, for example, U.S. Pat. No.5,202,241, which is incorporated herein in its entirety. The compound ofgeneral structural formula (ii) may be prepared by process A by the acidor base mediated rearrangement of compound (i) in the presence of waterand a suitable acid or base. The compound of general formula (iii) maybe prepared in process B from (ii) directly via reaction with azide oralternatively through a multi step process which includes removal of theester functionality through hydrolysis with a suitable base or acid,activation of the carboxylic acid moiety using a suitable activationagent, and reaction with a suitable reagent such as azide. Azidesrepresented by formula (iii) are known in the art and are readilysynthesized by standard procedures commonly employed in the art. Thecompound of general formula (iv) may be prepared by reaction of theazide (iii) with a nucleophile, alcohol, amine, or protecting group(X₁). A suitable protecting group can be selected by those skilled inthe art. Protecting groups are selected so that they are suitable forthe depicted transformations and can be removed following the synthesiswith little or no loss of yield. The introduction and selective removalof protecting groups are taught in Greene and Wuts, “Protective Groupsin Organic Synthesis”, John Wiley & Sons (1991). The compound of generalstructural formula (v) may be prepared by reacting compound (iv) with areactive reagent such as an electrophile, alkylating agent, acylatingagent, or protecting group (X₂) to afford compound (v). The compound ofgeneral structure (vi) can be prepared by reacting compound (v) withacid, base, a nucleophile, or electrophile to remove the protectinggroup (xi). The compound of general structure (vii) can be prepared byreacting compound (vi) with a suitable electrophile, alkylating agent,or acylating agent (X₃). The compound of general structure (viii) can beprepared by reacting compound (vii) with acid, base, a nucleophile, orelectrophile to remove the protecting group (X₂). Alternatively, any ofthese steps (A-G) may be performed in a different order, or with somesteps removed or slightly altered, which is obvious to those skilled inthe art.

Steps 1-3 Preparation of Acylazide (2)

To a solution of the ester (1, 1.5 g, 1.16 mmol) in THF (300 mL) isadded 20 mL H₂O and NaOH (60 mg, 1.50 mmol). The reaction is stirred at60° C. for 1.5 h and monitored by TLC (10% MeOH/DCM) and LCMS. Aftercompletion, the reaction is concentrated to dryness. The off-white solidis suspended in toluene (100 mL) and concentrated to dryness (repeat3×), which affords the acid, an off-white solid. The crude solid isstored in vacuo (0.1 Torr) for 12 h. LCMS: R_(t)=1.12 min, [M+H]⁺1125.

The crude acid is suspended in 300 mL acetone. The flask is sonicatedand the solid scraped down the sides of the flask for 15 min. To thissuspension is added TEA (2.0 mL, 14.2 mmol) and ethyl chloroformate (2.0mL, 20.91 mmol). The reaction appears to slowly dissolve. Furthersonication, and vigorous stirring is used to break up all particles.After 1 h, the reaction appears complete via LCMS and NaN₃ (500 mg, 7.69mmol) is added. The suspension (white/yellow in appearance) is stirredfor 1 h at 60° C. and monitored by LCMS. Two more aliquots of NaN₃ (500mg, 7.69 mmol) is added and the reaction stirs for 20 min. The reactionis concentrated onto SiO₂ and purified by flash chromatography(1.5″×1.5″ SiO₂ column, 3 L EtOAc). This affords 920 mg of crudeacyl-azide (2), a white solid. The crude material is taken on to thenext step with no further purification. LCMS: R_(t)=1.55 min,[M+H]⁺1150.

Step 4 Preparation of Boc-Amine (3)

A suspension of acyl-azide (2, 920 mg) is heated (80° C.) in t-BuOH (100g). After 2 h complete dissolution occurs and after 12 h the reactionappears complete by LCMS. The solution is concentrated directly ontoSiO₂ and chromatographed (gradient elution: 50-70% EtOAc/hexanes) whichaffords 600 mg of Boc-amine (3), a white solid. ¹H NMR (400 MHz,d₆-DMSO) δ 10.38 (br s, 1H), 9.00 (d, 1H), 8.70 (app d, 2H), 8.58 (s,1H), 8.44-8.41 (m, 1H), 8.38 (d, 1H), 8.23 (s, 1H), 8.11 (d, 1H), 7.48(br s, 1H), 7.38-7.23 (m, 7H), 6.02 (br s, 1H), 5.31-5.18 (m, 3H),5.01-5.00 (m, 1H), 4.97 (s, 2H), 4.30-4.24 (dd, 1H), 3.79 (dd, 1H), 3.38(s, 3H), 2.75-2.68 (m, 1H), 2.47 (d, 3H), 2.22-2.13 (m, 1H), 1.49 (s,9H), 1.37-1.31 (m, 1H), 0.87 (d, 3H), 0.84 (d, 3H). LCMS: R_(t)=1.72min, [M+H]⁺1196.

Step 5 Preparation of Boc-Amine-Acetate (4)

To a solution of the Boc-amine (3, 540 mg, 0.451 mmol) in DCM (250 mL)is added acetic anhydride (0.100 mL, 0.979 mmol), pyridine (1.0 mL, 12.4mmol) and DMAP (20 mg, 0.169 mmol). The reaction is stirred for 3 h,concentrated directly onto SiO₂ and chromatographed (gradient elution:50-70% EtOAc/hexanes) which provides 465 mg of Boc-amine-acetate (4). ¹HNMR (400 MHz, d₆-DMSO) δ 10.38 (br s, 1H), 9.20 (br d, 1H), 8.79 (br d,1H), 8.61 (br d, 1H), 8.56 (s, 1H), 8.44-8.41 (m, 1H), 8.38 (d, 1H),8.24 (s, 1H), 8.11 (d, 1H), 7.48 (br s, 1H), 7.42 (s, 2H), 7.35-7.29 (m,6H), 6.14 (s, 1H), 5.47 (t, 1H), 5.31-5.26 (m, 1H), 5.19 (dd, 1H), 4.97(s, 3H), 4.26 (dd, 1H), 3.72 (dd, 1H), 3.38 (s, 3H), 2.70-2.65 (m, 1H),2.59 (s, 3H), 2.45 (d, 3H), 2.22-2.14 (m, 1H), 1.96 (s, 3H), 1.57-1.50(m, 1H), 1.49 (s, 9H), 0.88 (d, 3H), 0.84 (d, 3H). LCMS: R_(t)=1.81 min,[M+H]⁺1238.

Example 1 Preparation of Amide (5)

To a solution of the Boc-amine (3, 10 mg, 0.0083 mmol) in DCM (10 mL) isadded TFA (1 mL, 13.46 mmol). The reaction is stirred for 30 min andconcentrated. The resultant yellow foam is dissolved in DCM (10 mL) andconcentrated (repeat 3×). The crude amine salt is taken on with nofurther purification. LCMS: R_(t)=1.33 min, [M+H]⁺1096.

To a solution of the amine (0.0083 mmol) in pyridine (1 mL) is addedacetic anhydride (0.100 mL, 0.979 mmol). The solution is stirred at RTfor 10 min and poured into a saturated aq solution of sodium bicarbonate(100 mL). The mixture is extracted with EtOAc (3×) and the combinedorganic extracts are dried over MgSO₄, filtered, and concentrateddirectly onto SiO₂. The crude product is purified by flashchromatography (gradient elution: 0-5% MeOH/DCM) to afford 6 mg of amide(5) as a white solid. ¹H NMR (400 MHz, d₆-DMSO) δ 11.14 (br s, 1H), 9.00(br d, 1H), 8.68-8.66 (m, 2H), 8.59 (s, 1H), 8.45-8.42 (m, 1H), 8.40 (d,1H), 8.24 (s, 1H), 8.13 (d, 1H), 7.80 (s, 1H), 7.38-7.21 (m, 7H), 6.01(br d, 1H), 5.32-5.17 (m, 3H), 5.01-4.99 (m, 1H), 4.97 (s, 2H), 4.27(dd, 1H), 3.79 (dd, 1H), 3.38 (s, 3H), 2.73-2.68 (m, 1H), 2.46 (d, 3H),2.19-2.14 (m, 1H), 2.10 (s, 3H), 1.35-1.28 (m, 1H), 0.87 (d, 3H), 0.84(d, 3H). LCMS: R_(t)=1.35 min, [M+H]⁺1138.

Example 2 Preparation of Methyl Ester (6)

Methyl ester (6) is prepared according to the procedures described inexample 1, except adipic acid monomethylester chloride is used as anacylating agent. ¹H NMR (400 MHz, d₆-DMSO) δ 11.11 (br s, 1H), 9.00 (brs, 1H), 8.68-8.66 (m, 2H), 8.59 (s, 1H), 8.44-8.41 (m, 1H), 8.40 (d,1H), 8.24 (s, 1H), 8.13 (d, 1H), 7.83 (s, 1H), 7.38-7.22 (m, 8H), 6.02(br d, 1H), 5.31-5.17 (m, 3H), 5.01-4.99 (m, 1H), 4.97 (s, 2H), 4.28(dd, 1H), 3.78 (dd, 1H), 3.59 (s, 3H), 3.38 (s, 3H), 2.70 (m, 1H), 2.58(s, 3H), 2.46 (d, 3H), 2.40 (app t, 2H), 2.34 (app t, 2H), 2.20-2.12 (m,1H), 1.65-1.54 (m, 4H), 1.35-1.32 (m, 1H), 0.87 (d, 3H), 0.84 (d, 3H).LCMS: R_(t)=1.47 min, [M+H]⁺1238.

Example 3 Preparation of Acid (7)

Steps 1-2 Preparation of Methylester-Acetate (8)

To a solution of Boc-amine-acetate (4, 190 mg, 0.153 mmol) in DCM (10mL) is added TFA (5 mL, 67.3 mmol). The reaction is stirred for 30 minand concentrated. The resultant yellow foam is dissolved in DCM (10 mL)and concentrated (repeat 3×). The crude amine salt is taken on with nofurther purification. LCMS: R_(t)=1.45 min, [M+H]⁺1138.

To a solution of the amine salt in pyridine (5 mL) is added adipic acidmonomethyl ester chloride (0.200 mL, 1.285 mmol). The solution isstirred at RT for 10 min and poured into a saturated aq solution ofsodium bicarbonate (100 mL). The mixture is extracted with EtOAc (3×)and the combined organic extracts were dried over MgSO₄, filtered, andconcentrated directly onto SiO₂. The crude product is purified by flashchromatography (gradient elution: 50-80% EtOAc/hexanes) which affords170 mg of ester-acetate (8). LCMS: R_(t)=1.58 min, [M+H]⁺1280.

Step 3 Preparation of Acid (7)

To a solution of the methylester-acetate (8, 170 mg, 0.133 mmol) in MeOH(100 mL) is added H₂O (5 mL) and NaOH (100 mg, 2.5 mmol). The solutionis heated to 50° C., stirred for 2 h, and concentrated onto SiO₂. Flashchromatography (gradient elution: 0-5% MeOH/DCM) provides 95 mg of thetitle compound, a tan solid. ¹H NMR (400 MHz, d₆-DMSO) δ 12.05 (br s,1H), 11.13 (br s, 1H), 9.44 (br d, 1H), 8.70-8.65 (m, 2H), 8.59 (s, 1H),8.45-8.42 (m, 1H), 8.39 (d, 1H), 8.23 (s, 1H), 8.13 (d, 1H), 7.82 (s,1H), 7.42-7.38 (m, 1H), 7.32 (s, 1H), 7.29-7.17 (m, 6H), 6.13 (br s,1H), 5.33-5.17 (m, 3H), 5.03 (d, 1H), 4.98 (s, 3H), 4.32 (dd, 1H),3.83-3.76 (m, 1H), 3.38 (s, 3H), 2.74-2.68 (m, 1H), 2.58 (s, 3H), 2.47(d, 3H), 2.40 (t, 2H), 2.23 (t, 2H), 2.19-2.14 (m, 1H), 1.66-1.52 (m,4H), 1.34-1.29 (m, 1H), 0.87 (d, 3H), 0.74 (d, 3H). LCMS: R_(t)=1.24min, [M+H]⁺1224.

Example 4 Preparation of Trifluoroacetate (9)

Steps 1-2 Preparation of Acetate (10)

To a solution of Boc-amine-acetate (4, 400 mg, 0.323 mmol) in DCM (25mL) is added TFA (5 mL, 67.3 mmol). The reaction is stirred for 30 minand concentrated. The resultant yellow foam is dissolved in DCM (10 mL)and concentrated (repeat 3×). The crude amine salt is taken on with nofurther purification. LCMS: R_(t)=1.45 min, [M+H]⁺1138.0.

To a solution of the amine (0.323 mmol) in pyridine (5 mL) is addedmethanesulfonylchloride (0.050 mL, 0.646 mmol). The solution is stirredfor 30 min and poured into a saturated aq solution of sodium bicarbonate(100 mL). The mixture is extracted with EtOAc (3×) and the combinedorganic extracts are dried over MgSO₄, filtered, and concentrateddirectly onto SiO₂. The crude product is purified by flashchromatography (gradient elution: 50-80% EtOAc/hexanes) which afforded330 mg of acetate (10). LCMS: R_(t)=1.67 min, [M+H]⁺1234.0.

Step 3 Preparation of Trifluoroacetate (9)

To a solution of the acetate (10, 200 mg, 0.162 mmol) in MeOH (50 mL) isadded K₂CO₃ (50 mg, 0.362 mmol). The reaction is stirred for 10 min andconcentrated. The solid is suspended in EtOAc and poured into asaturated aq solution of sodium bicarbonate (100 mL). The mixture isextracted with EtOAc (3×) and the combined organic extracts are driedover MgSO₄, filtered, and concentrated directly onto SiO₂. The crudeproduct is purified by HPLC (method 1) which affords 55 mg of acetate(9). ¹H NMR (400 MHz, d₆-DMSO) δ 12.78 (br s, 1H), 9.00 (br d, 1H),8.69-8.67 (m, 2H), 8.59 (s, 1H), 8.43-8.41 (m, 2H), 8.27 (s, 1H), 8.19(d, 1H), 8.02 (s, 1H), 7.39-7.21 (m, 7H), 5.32-5.17 (m, 3H), 5.00 (d,1H), 4.97 (s, 2H), 4.28 (dd, 1H), 3.79 (dd, 1H), 3.38 (s. 3H), 2.70 (m,1H), 2.71 (m, 1H), 2.58 (s, 3H), 2.47 (d, 3H), 2.20-2.12 (m, 1H),1.34-1.27 (m, 1H), 0.87 (d, 3H), 0.84 (d, 3H). LCMS: R_(t)=1.56 min,[M+H]⁺1192.

Example 5 Preparation of Sulfonamide (11)

Steps 1-2 Preparation of Acetate (12)

To a solution of Boc-amine-acetate (4, 100 mg, 0.081 mmol) in DCM (25mL) is added TFA (5 mL, 67.3 mmol). The reaction is stirred for 30 minand concentrated. The resultant yellow foam is dissolved in DCM (10 mL)and concentrated (repeat 3×). The crude amine salt is dissolved in EtOAcand poured into a saturated aq solution of sodium bicarbonate (100 mL).The mixture is extracted with EtOAc (3×) and the combined organicextracts are dried over MgSO₄, filtered, and concentrated. The crudefree-based amine is taken on with no further purification. LCMS:R_(t)=1.45 min, [M+H]⁺1138.

To a solution of the amine (0.081 mmol) in pyridine (5 mL) is addedmethanesulfonylchloride (0.050 mL, 0.646 mmol). The solution is stirredfor 30 min and poured into a saturated aq solution of sodium bicarbonate(100 mL). The mixture is extracted with EtOAc (3×) and the combinedorganic extracts are dried over MgSO₄, filtered, and concentrateddirectly onto SiO₂. The crude acetate (12) is taken on to the next stepwithout any further purification. LCMS: R_(t)=1.42 min, [M+H]⁺1216.

Step 3 Preparation of Sulfonamide (11)

To a solution of the sulfonamide (12) in MeOH (10 mL) is added K₂CO₃ (50mg, 0.362 mmol). The reaction is stirred 5 min, concentrated, andpurified by HPLC (method 2) to afford 15 mg of sulfonamide 11. ¹H NMR(400 MHz, d₆-DMSO) δ 10.62 (br s, 1H), 9.00 (br d, 1H), 8.68-8.66 (m,2H), 8.58 (s, 1H), 8.44-8.41 (m, 1H), 8.37 (d, 1H), 8.23 (s, 1H), 8.15(d, 1H), 7.39-7.20 (m, 7H), 7.07 (br s, 1H), 6.02 (d, 1H), 5.31-5.18 (m,3H), 5.01-4.98 (m, 1H), 4.97 (s, 2H), 4.27 (dd, 1H), 3.77 (dd, 1H), 3.38(s, 3H), 3.12 (s, 3H), 2.73-2.67 (m, 1H), 2.58 (s, 3H), 2.47 (d, 3H),2.19-2.13 (m, 1H), 1.36-1.28 (m, 1H), 0.87 (d, 3H), 0.84 (d, 3H). LCMS:R_(t)=1.31 min, [M+H]⁺1174.

Example 6 Preparation of Amine (13)

Steps 1-2 Preparation of Boc-Amine (14)

The preparation of Boc-amine (14) is performed according to the methoddescribed in example 3, except the acid chloride of5-(tert-butoxycarbonylamino)-valeric acid is used as an acylating agent.LCMS: R_(t)=1.66 min, [M+2H]⁺1338.

Step 3 Preparation of Amine (13)

To a solution of Boc-amine (14, 150 mg, 0.112 mmol) in DCM (5 mL) isadded TFA (2 mL, 26.9 mmol). The solution is stirred for 30 min andconcentrated directly onto SiO₂. Flash chromatography (gradient elution:0-10% MeOH/DCM, then 100% DCM, then 0-10% MeOH/DCM with 0.1% AcOH)furnishes 90 mg of amine 13. ¹H NMR (400 MHz, d₆-DMSO) δ 11.16 (br s,1H), 9.23 (br d, 1H), 8.77 (br d, 1H), 8.62 (br d, 1H), 8.58 (s, 1H),8.44-8.42 (m, 1H), 8.40 (d, 1H), 8.25 (s, 1H), 8.14 (d, 1H), 7.84 (s,1H), 7.73-7.64 (m, 2H), 7.41 (s, 1H), 7.35-7.31 (m, 5H), 7.28-6.95 (m,2H), 6.14 (d, 1H), 5.46 (t, 1H), 5.29-5.25 (m, 1H), 5.19 (dd, 1H), 4.97(s, 2H), 4.26 (dd, 1H), 3.72 (dd, 1H), 3.38 (s, 3H), 2.85-2.79 (m, 2H),2.71-2.65 (m, 2H), 2.59 (s, 1H), 2.46 (d, 3H), 2.44-2.42 (m, 2H),2.22-2.15 (m, 1H), 1.96 (s, 3H), 1.70-1.56 (m, 4H), 1.50-1.42 (m, 1H),0.88 (d, 3H), 0.84 (d, 3H). LCMS: R_(t)=1.06 min, [M+2H]⁺1238.

Example 7 Preparation of Amine (15)

Boc-amine (14) is prepared as described in example 6. The acetateprotecting group is then removed according to the procedures describedin example 4. The boc protecting group is removed according to theprocedures described in example 6. HPLC purification (method 1)furnishes the amine (15). ¹H NMR (400 MHz, d₆-DMSO) δ 11.16 (s, 1H),9.02, (br d, 1H), 8.70-8.65 (m, 2H), 8.60 (s, 1H), 8.45-8.41 (m, 1H),8.40 (d, 1H), 8.24 (s, 1H), 8.13 (d, 1H), 7.84 (s, 1H), 7.69-7.62 (br s,3H), 7.38-7.20 (m, 7H), 6.03 (br s, 1H), 5.31-5.18 (m, 3H), 5.02-4.99(m, 1H), 4.97 (s, 2H), 4.28 (dd, 1H), 3.78 (dd, 1H), 3.38 (s, 3H),3.12-3.06 (m, 4H), 2.84-2.79 (m, 2H), 2.73-2.69 (m, 1H), 2.58 (s, 3H),2.47 (d, 3H), 2.46-2.42 (d, 3H), 2.20-2.12 (m, 1H), 1.70-1.54 (m, 4H),1.29-1.22 (m, 1H), 1.17 (t, 6H), 0.87 (d, 3H), 0.84 (d, 3H). LCMS:R_(t)=0.93 min, [M+2H]⁺1196.

Example 8 Preparation of Amide (16)

Amide (16) is prepared according to the procedures described in example3. ¹H NMR (400 MHz, d₆-DMSO) δ 10.69 (s, 1H), 9.00 (br d, 1H), 8.68-8.66(m, 2H), 8.59 (s, 1H), 8.45-8.41 (m, 1H), 8.40 (d, 1H), 8.25 (s, 1H),8.16 (d, 1H), 7.87 (s, 1H), 7.39-7.21 (m, 7H), 6.03 (br s, 1H),5.31-5.18 (m, 3H), 5.01-4.99 (m, 1H), 4.97 (s, 2H), 4.27 (dd, 1H), 4.18(s, 2H), 3.78 (dd, 1H), 3.70-3.68 (m, 2H), 3.63-3.59 (m, 4H), 3.52-3.50(m, 2H), 3.38 (s, 3H), 3.24 (s, 3H), 2.73-2.68 (m, 1H), 2.58 (s, 3H),2.47 (d, 3H), 2.20-2.12 (m, 1H), 1.35-1.28 (m, 1H), 0.87 (d, 3H), 0.84(d, 3H). LCMS: R_(t)=1.45 min, [M+H]⁺1256.

Example 9 Preparation of Acid (17)

Step 1 Preparation of Amide (18)

To a solution of Boc-amine-acetate (3, 200 mg, 0.167 mmol) in DMF (5 mL)is added Cs₂CO₃ (100 mg, 0.309 mmol) and iodomethane (0.100 mL, 1.61mmol, neutralized with Al₂O₃). The solution is stirred for 2 h,concentrated, and taken on to the next step with no furtherpurification. LCMS: R_(t)=1.85, [M+H]⁺1210.

Steps 2-4 Preparation of Acid (17)

Acid (17) is prepared according to the procedures described in example3. ¹H NMR (400 MHz, d₆-DMSO) δ 9.01 (br d, 1H), 8.69-8.66 (m, 2H), 8.59(s, 1H), 8.45-8.41 (m, 1H), 8.38 (d, 1H), 8.26 (s, 1H), 8.22 (d, 1H),7.92 (br s, 1H), 7.39-7.20 (m, 8H), 5.31-5.18 (m, 3H), 5.00-4.99 (m,1H), 4.97 (s, 2H), 4.27 (dd, 1H), 3.81-3.76 (dd, 1H), 3.38 (s, 3H), 3.34(br s, 3H), 2.73-2.68 (m, 1H), 2.58 (s, 3H), 2.47 (d, 3H), 2.46-2.40 (m,2H), 2.26-2.41 (m, 2H), 2.19-2.12 (m, 1H), 1.80-1.73 (m, 2H), 1.33-1.25(m, 1H), 0.88 (d, 3H), 0.84 (d, 3H). LCMS: R_(t)=1.27, [M+H]⁺1224.

Example 10 Preparation of Acid (19)

Acid (19) is prepared according to the procedures described in example3. ¹H NMR (DMSO-d₆) δ11.22 (s, 1H), 9.27 (d, 1H), 8.65-8.69 (m, 2H),8.58 (s, 1H), 8.42-8.45 (m, 1H), 8.38 (d, 1H), 8.23 (s, 1H), 8.13 (d,1H), 7.83 (s, 1H), 7.19-7.46 (m, 8H), 6.42 (br s, 1H), 5.18-5.30 (m,3H), 5.02 (d, 1H), 4.98 (s, 2H), 4.27-4.34 (m, 1H), 3.77-3.82 (m, 1H),3.38 (s, 3H), 2.69-2.74 (m, 2H), 2.58 (s, 3H), 2.41-2.46 (m, 5H),2.14-2.23 (m, 3H), 1.79-1.85 (m, 2H), 1.28-1.34 (m, 1H), 0.83-0.88 (m,6H). LCMS: R_(t)=1.18, [M+H]⁺1210.

Example 11 Preparation of Acid (20)

Acid (20) is prepared according to the procedures described in example3. ¹H NMR (DMSO-d₆) δ11.18 (s, 1H), 9.00 (d, 1H), 8.67 (d, 2H), 8.59 (s,1H), 8.42 (d, 2H), 8.24 (s, 1H), 8.14 (d, 1H), 7.80 (s, 1H), 7.22-7.38(m, 8H), 5.18-5.31 (m, 3H), 5.00 (d, 1H), 4.97 (s, 2H), 4.24-4.30 (m,1H), 3.75-3.81 (m, 1H), 3.38 (s, 3H), 2.63-2.73 (m, 2H), 2.58 (s, 3H),2.53-2.56 (m, 1H), 2.46-2.48 (m, 5H), 2.13-2.19 (m, 1H), 1.29-1.35 (m,1H), 0.83-0.88 (m, 6H). LCMS: R_(t)=1.22 min, [M+H]⁺1196.

Example 12 Preparation of Amine (21)

Amine (21) is prepared according to the procedures in example 7. ¹H NMR(DMSO-d₆) δ 9.01 (d, 1H), 8.65-8.69 (m, 2H), 8.59 (s, 1H), 8.39-8.44 (m,2H), 8.24 (s, 1H), 8.13 (d, 1H), 7.83 (s, 1H), 7.20-7.37 (m, 8H), 6.02(d, 1H), 5.18-5.31 (m, 3H), 5.00 (d, 1H), 4.97 (s, 2H), 4.24-4.30 (m,1H), 3.76-3.81 (m, 1H), 3.38 (s, 3H), 2.66-2.72 (m, 3H), 2.58 (s, 3H),2.44-2.4 (m, 5H), 2.14-2.18 (m, 1H), 1.72-1.79 (m, 2H), 1.24-1.33 (m,1H), 0.83-0.88 (m, 6H). LCMS: R_(t)=0.86, [M+H]⁺1181.

Example 13 Preparation of Aminothiazole Hydrochloric Acid (22)

Hydrochloric acid is bubbled through a solution of Boc protected amine(4, 1.4 g, 1.1 mmol) in DCM (20 mL) for thirty min. The reaction mixtureis then tightly capped and stirred for thirty minutes after which thereaction mixture is sparged with nitrogen. The mixture loses its gellike appearance. DCM (5 mL) is added to the solution, and HCl gas isbubbled through it for an additional 20 min, followed by nitrogen for 30min. Crude product (1.32 g) is obtained after concentration as a brightorange solid, and taken on to the next step with no furtherpurification. LCMS: R_(t)=1.5 min, [M+H]⁺1138.

Example 14 Preparation of Acid (23)

Step 1 Coupling Reactions Using N-Cyclohexylcarbodiimide, N′-MethylPolystyrene

To a solution of aminothiazole hydrochloric acid (22, 348 mg, 1 eq) inDCM (20 mL) and pyridine (0.5 mL) is added R-(−)-4-methylglutaric acid1-monomethyl ester (72.0 μL, 0.45 mmol, 2 eq) andN-cyclohexylcarbodiimide, N′-methyl polystyrene (348 mg, 0.90 mmol, 3eq). The reaction mixture is stirred for 4 h, then the solution isfiltered through Celite and concentrated.

Step 2 Deprotection of Acetate and Saponification to Acid

The concentrate is dissolved in THF (5.0 mL), MeOH (5.0 mL), and water(2.0 mL). To this solution is added 4 M LiOH (0.34 mL, 3.96 mmol).Ammonium chloride (sat. aq) is added to neutralize excess LiOH, and thesolution is concentrated onto silica. The crude residue is firstchromatographed with 10% MeOH in DCM (isochratic). A secondchromatography (gradient elution: 0-10% MeOH/DCM) affords product 23.HRMS [M+H]⁺1224.2688. LC R_(t)=14.85 min.

Example 15 Preparation of Amino-Acid (24)

Step 1

Conditions for the amide coupling for 24 are the same as example 14,step 1 with Boc-(L) glutamic acid t-butyl ester (27.3 mg, 0.09 mmol).

Step 2

The procedure in example 5 is used to remove the acetate protectinggroup. Flash chromatography (50-80% ethylacetate/hexanes) yields 239 mgyellow solid.

Step 3 Deprotection of Boc and T-Butyl Groups

The material is dissolved in DCM (50 mL) and HCl gas is bubbled throughthe solution for 10 min. The solution is then sparged with nitrogen toremove excess acid. Purification via HPLC yields 24 (9 mg). LCMS:R_(t)=0.99 min, [M+2H]⁺ 1226

Example 16 Preparation of Sulfonamide (25)

Step 1

To a solution of the aminothiazole hydrochloride salt (22, 1.0 g, 0.85mmol) in pyridine (30 mL) is added 2-phthalimidoethanesulfonyl chloride(700 mg, 2.6 mmol). The reaction is stirred for 2 h. Additional sulfonylchloride is added (236 mg, 1.3 mmol). After stirring 30 min the mixtureis concentrated onto silica gel and purified via flash chromatography(gradient elution: 50-100% EtOAc/hexanes) affording product (500 mg).

Step 2 Deprotection of Phthalimide Amine

To a solution of the sulfonamide in MeOH (30 mL) is added hydrazinehydrate (0.5 mL). The reaction is stirred for 1 h and the mixture isconcentrated onto silica gel and purified first via flash chromatography(gradient elution: 0-10% MeOH/DCM then 1% NH₄OH+10% MeOH/DCM). A secondpurification is performed with a Biotage column C18 (gradient elution:10-70% CH₃CN/H₂O with 0.01% TFA) providing the TFA salt (10.4 mg) as awhite solid. HRMS: 1203.1965, LC R_(t)=12.33 min.

Example 17 Preparation of Phosphoric-Acid (26)

Step 1

The amide synthesis of compound 26 is performed according to theprocedure described above using diethylphosphonopentanoic acid (0.2 mL)and PS-DCC.

Step 2 Deprotecting the Phosphoric Acid

To a cooled solution of the phosphoric ester (275 mg, 0.21 mmol) in DCM(50 mL) at 0° C. is added TMSBr (1 mL, >100 eq). The mixture is stirredfor 1 h, then warmed to RT. TMSBr (2 mL, >100 eq) is added and thesolution is stirred at RT for 1 h. The mixture is concentrated todryness, and the crude phosphoric acid is taken forward with no furtherpurification.

Step 3

The acetate removal is performed according to the procedure describedabove. Purification is performed on a C18 biotage column. Twopurifications are performed (gradient elution: 20-80% acetonitrile/waterwith 0.1% TFA; second column 20-80% acetonitrile/water with 0.1%) toafford product 26. HRMS: m/2=630.6124, LC R_(t)=13.24 min.

Example 18 Preparation of Alcohol (27)

To a 0° C. solution of acid 23 (1.0 g, 0.82 mmol) in THF (20 mL) isadded Et₃N (0.11 mL, 0.82 mmol) followed by ethylchloroformate (0.08 mL,0.89 mmol). The mixture is stirred for 30 min, then warmed to RT andstirred for an additional 30 min. The triethylamine hydrochloride saltis filtered off and the solution is cooled again to 0° C. NaBH₄ (68 mg,1.8 mmol) in water (3 mL) is added. The mixture is stirred for 30 min,warmed to RT and stirred for an additional 30 min. The mixture isneutralized with 1 N HCl and partitioned with DCM. The organic extractis collected and concentrated. The product is purified viachromatography: column 1, Biotage C18 column, gradient elution 20-70%acetonitrile/water with 0.1% TFA. A second purification repeats theconditions of column 1. A third purification uses a Biotage C18 column(gradient elution: 20-70% acetonitrile/water with 0.1% ammonium formate)to provide product. LCMS R_(t)=1.37 min, [M+H]⁺1210.

Example 19 Preparation of Acid (28)

Step 1

The amide synthesis of compound 28 is performed according to the PS-DCCprocedure described above usingtrans-4-carbomethoxycyclohexane-1-carboxylic acid (316 mg, 1.70 mmol).

Step 2

Deprotection of the acetate and saponification for the synthesis of 28is performed according to the procedures described above. Purificationvia flash chromatography (isochratic elution: 10% MeOH/DCM), then viaHPLC provides 28 (100 mg) as a light yellow solid. LCMS: R_(t)=1.37 min,[M+H]⁺=1250.

Example 20 Preparation of Amino-Amide (29)

To a solution of 28 (470 mg, 0.38 mmol) in acetone (20 mL), water (30μL) and Et₃N (0.2 mL, 1.5 mmol) is added ethylchloroformate (0.07 mL,0.75 mmol). The solution is stirred for 1 h and ethylenediamine (0.5 mL,7.5 mmol) is added. The crude solution is then concentrated onto silicagel and purified via flash chromatography (gradient elution: 0-20%MeOH/DCM) then via HPLC to yield product as a yellow solid. LCMS:R_(t)=0.94 min, [M−H]⁺1290.

Example 21 Preparation of Carbamate (30)

Step 1

To a suspension of acylazide 2 (1.15 g, 1.00 mmol) in toluene (60 mL) isadded alcohol (0.354 g, 3.00 mmol) and the mixture is stirred at 80° C.for 4 h. The reaction is concentrated in vacuo and the crude product ispurified by flash chromatography (heptane/EtOAc) to yield 1.01 g (0.815mmol, 81.5%) of the intermediate ester.

Step 2

To a solution of the ester (1.01 g, 0.815 mmol) in MeOH (25 mL) andwater (3 mL) is added sodium hydroxide (0.325 g, 8.13 mmol) and themixture is stirred at 22° C. for 16 h. The reaction is concentrated invacuo and the crude product is purified by flash chromatography(MeOH/DCM) to yield 0.705 g (0.575 mmol, 71%) of 30. LC: R_(t)=14.83min, HRMS: [M+H]⁺1226.2257.

Example 22 Preparation of Carbamoyl-Acid (31)

Step 1

To a suspension of acylazide (2, 0.600 g, 0.522 mmol) in toluene (20 mL)is added trans-4-hydroxy-cyclohexanecarboxylic acid ethylester (0.134 g,0.778 mmol) and the mixture is stirred at 80° C. for 5 h. The reactionis concentrated in vacuo and the crude product is purified by flashchromatography (MeOH/DCM) to yield 0.236 g (0.182 mmol, 35%) of theester.

Step 2

To a solution of the ester (0.236 g, 0.182 mmol) in THF (3.6 mL) and H₂O(1.2 mL) is added lithium hydroxide (0.045 g, 1.29 mmol) and the mixtureis stirred at 22° C. for 48 h. The reaction is concentrated in vacuo andthe crude product is purified by flash chromatography (MeOH/DCM) toyield 0.119 g (0.094 mmol, 52%) of 31. Further purification via HPLC(30×100 mm C₁₈ Waters Sunfire, gradient elution 30-80% ACN/H₂O, 0.1%TFA, 6 mL/min for 9 min) affords 31. LC: R_(t)=12.98 min. HRMS: m/2,[M+2H]⁺633.6321.

Example 23 Preparation of Urea (32)

Step 1

To a solution of amine 22 (0.115 g, 0.101 mmol) in pyridine (4 mL) isadded the 3-isocyanaopropionic acid ethylester (0.452 mL, 0.343 mmol)and the mixture is stirred at 22° C. for 1 h. The reaction isconcentrated in vacuo and the residue is azeotroped with toluene toprovide 0.129 g (0.101 mmol) of the acetate-ester of 32. LCMS: m/2[M+2H]⁺641.

Step 2

To a solution of the acetate (0.129 g, 0.101 mmol) in MeOH (4 mL) isadded K₂CO₃ (42 mg, 0.303 mmol) and the mixture is stirred for 2 h at22° C. NaOH (s, 100 mg, 2.5 mmol) in H₂O (2 mL) is added via syringe andreaction mixture is stirred for 24 h. The volatiles are removed underreduced pressure. The residue is purified by HPLC (30-80% ACN/H₂O, 0.1%TFA) to provide 30 mg (25%) of yellow solid, 32. LC: R_(t)=16.69 min, MS[M+H]⁺ 1211.

Example 24 Preparation of Sulfonylurea (33)

Step 1

To a solution of chlorosulfonylisocyanate (1.35 g, 9.6 mmol) in DCM (50mL) at 0° C., is added t-BuOH (918 uL, 9.6 mmol) and stirred for 30 minwhile maintaining temperature at 0° C. To a solution of amine 22 (820mg, 0.72 mmol) in pyridine (12 mL) is added 0.2 M solution of sulfonylchloride (1.44 mmol, 0.72 mL). The reaction is stirred for 5 min at 0°C. The solvents were evaporated in vacuo and the solid is purified bybasic alumina flash chromatography (gradient elution: 0-10% MeOH/DCM toprovide 220 mg of the boc-sulfonylurea. MS (M+H)⁺ 1317.

Step 2

To a solution of the intermediate boc-sulfonylurea (106 mg, 0.08 mmol)in MeOH (10 mL) is added K₂CO₃ (111 mg, 0.8 mmol). The reaction isstirred for 2 h at 22° C. 1 g of SiO₂ is added to the reaction and thesolvents are evaporated in vacuo. The solid is purified by flashchromatography (gradient elution: 0-10% MeOH/DCM) to provide 102 mg of ayellow solid. The yellow solid (120 mg, 0.09 mmol) is dissolved in DCM(20 mL), cooled to 0° C. and HCl (g) is bubbled into the solution for 10min. The reaction is capped and stirred for 2 h. N₂ gas is bubbled intoreaction to remove excess HCl gas. The solvents are evaporated in vacuoto provide 140 mg crude yellow solid. The solid was purified by HPLCpurification (gradient elution: 30-50% ACN/H₂O, 0.1% TFA) to provide 11mg of 60% pure solid. Second HPLC purification (gradient elution: 50-55%ACN/H₂O, 0.1% TFA) provides 6.7 mg of product 33. LCMS: R_(t) 1.24 min,(M+H)⁺ 1175.

Example 25 Preparation of Imidazole (37)

Step 1

To a suspension of boc-amine 4 (800 mg, 0.647 mmol) in DCM (150 mL) isadded HCl (g, stream) for 20 min. The reaction is capped and stirred for30 min. The reaction is concentrated to dryness and taken to the nextstep with no further purification. The residue is suspended in DCM (150mL) and a solution of formic acid in acetic anhydride (1 mL, 3:2) isadded followed by stirring at RT for 2 h. The crude formamide (34) isconcentrated to dryness and stored in vacuo for 12 h. LCMS: R_(t) 1.46min, [M+H]⁺ 1166.

Step 2

To a suspension of the intermediate formamide (34, 670 mg) in DCM (100mL) is added DIPEA (1 mL, 5.74 mmol) and POCl₃ (100 μL, 1.27 mmol). Thereaction is stirred at RT for 30 min and a second addition of DIPEA (1mL, 5.74 mmol) and POCl₃ (100 μL, 1.27 mmol) is added. The reaction isstirred an additional 30 min and then concentrated onto silica gel.Purification by flash chromatography (gradient elution: 60-100% EtOAc inheptane) affords 150 mg of isonitrile (35). LCMS: R_(t) 1.72 min, [M]1148.

Step 3

To a solution of isonitrile (35, 100 mg, 0.087 mmol) in THF (8 mL) isadded Cu₂O (cat.), ethyl isocyanoacetate (13.8 mg, 0.122 mmol) andphenanthroline (3.1 mg, 0.017 mmol). The reaction is placed in a sealedtube and heated to 80° C. for 2 h, then cooled to RT. The reaction isconcentrated and is purified by flash chromatography (gradient elution:50-100% EtOAc in heptane); second column: (gradient elution: 0-10% MeOHin DCM) to furnish imidzole-ester 36. LCMS: R_(t) 1.62 min, [M+2H]⁺1262.

Step 4

To a solution of imidazole 36 in MeOH (8 mL) and H₂O (2 mL) is addedNaOH (s, 10 mg, 0.25 mmol) and reaction is heated to 40° C. for 12 h.The reaction is cooled to RT and concentrated to dryness. Finalpurification by HPLC (gradient elution: 45-55% acetonitrile in H₂O with0.1% TFA) generates 3 mg of 37 as a TFA salt. LCMS: R_(t) 1.13 min,[M+H]⁺1191.

Example 26 Preparation of Imidazole (38)

Step 1

To a suspension of crude imidazole 37 (180 mg, 0.151 mmol) in DCM (10mL) and pyridine (500 μL) is added PS-DCC (0.453 mmol) and amino-aceticacid methyl ester (20 mg, 0.227 mmol). The reaction is stirred at RT for48 h and then heated to 40° C. for 2 h. The residue is concentrated ontosilica gel and purified by flash chromatography (gradient elution:50-100% EtOAc in heptanes) to generate 77 mg of methyl esterintermediate. LCMS: R_(t) 1.35 min, [M+H]⁺1262.

Step 2

The methyl ester (77 mg, 0.061 mmol) is suspended in MeOH (5 mL) and H₂O(1 mL) NaOH (s, 40 mg, 1.00 mmol) is added. The reaction is stirred atRT for 12 h and then concentrated onto silica gel for purification byflash chromatography (gradient elution: 0-10% MeOH in DCM+0.1% aceticacid) to generate 4.2 mg of imidazole acid 38. LCMS: R_(t) 1.18 min,[M+2H]⁺ 1249.

Example 26 Preparation of Imidazole (39)

Step 1

To a suspension of crude imidazole acid 37 (276 mg, 0.232 mmol) in DCM(20 mL) and pyridine (1.0 mL) is added PS-DCC (0.695 mmol) and(R)-pyrrolidine-2-carboxylic acid methyl ester (60 mg, 0.463 mmol). Thereaction is stirred and heated to 40° C. for 24 h. The reaction isconcentrated onto silica gel and purified (twice) by flashchromatography (gradient elution: 0-5% MeOH in DCM) to generate 170 mgof methyl ester intermediate. LCMS: R_(t) 1.45 min, [M+2H]⁺ 1303.

Step 2

The methyl ester (170 mg, 1.305 mmol) is suspended in MeOH (10 mL) andH₂O (2 mL) and NaOH (s, 40 mg 1.00 mmol) are added. The reaction isstirred at RT for 18 h then heated to 40° C. for 12 h. The reaction ismounted onto silica gel for purification by flash chromatography(gradient elution: 0-10% MeOH in DCM) followed by HPLC purification(gradient elution: 40-60% acetonitrile in H₂O with 0.1% TFA) to generate5 mg of imidazole acid 39. LCMS: R_(t) 1.11 min, [M+H]⁺ 1288.

Biological Results:

Using the standard MIC test described above with the bacteriaEnterococcus faecalis, Enterococcus faecium or Staphylococcus aureus,compounds 5-7, 9, 11, 13, 15-17, 19-21, 23-25, 27-33, 37-39 demonstratea minimum inhibitory concentration ranging from 0.0010 μg/mL to 128μg/mL.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and methods described herein. Such equivalents are intendedto be encompassed by the scope of the following claims.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications andother references cited herein are hereby expressly incorporated hereinin their entireties by reference.

1. A compound of the formula I:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof; wherein A is selected from thegroup consisting of a bond, H, —(CH₂)—, —C(alkyl)₂-, —(CH₂)₁₋₈—,—[C(alkyl)₂]₁₋₈—, -(cycloalkyl)-, -(aryl)-, -(heteroaryl)-, —C(O)—,—C(O)C(O)—, —C(O)O—, —C(O)N(R^(8a))—, —S(O)₂—, —S(O)—, —S(O)₂N(R^(8a))—,—S(O)N(R^(8a))—, —C(═NR⁸)N(R^(8a))—, —C(═NR⁸)N(R^(8a))C(O)—, —C(═NR⁸)—,—C═C—C(O)—, —C═C—C(O)O—, —C═C—C(O)N(R^(8a))—; G is absent, or selectedfrom the group consisting of H, —[C(R^(a))(R^(b))]_(x)—,—[C(R^(a))(R^(b))]_(x)—O—[C(R^(a))(R^(b))]_(y)—,—[C(R^(a))(R^(b))]_(x)—N(R^(8a))—[C(R^(a))(R^(b))]_(y)—, -(cycloalkyl)-,-(heterocycle)-, -(aryl)-, -(heteroaryl)-; J is selected from the groupconsisting of H, F, O-alkyl, N(R^(8a))₂, N⁺(R^(8a))₃,N(R^(8a))C(O)alkyl, CO₂H, C(═O)N(R^(8a))₂, CO₂-alkyl, P(O)(OH)₂,P(O)(O-alkyl)₂, and a substituted nitrogen-containing heterocycle; R^(a)is selected from the group consisting of H, alkyl, F, CO₂H, CO₂-alkyl,—N(R¹)₂, —OR¹, —(CH₂)₀₋₄-J and —R^(4b); R^(b) is selected from the groupconsisting of H, alkyl, and F; x and y are each, independently, integersfrom 0-10; R¹ is selected from —H, —C(alkyl)₂-J, —R^(4b). R^(2a) isselected from the group consisting of H, substituted or unsubstitutedalkyl, OH, OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ and N(R^(8a))₂; R^(2b)is selected from the group consisting of absent, H and alkyl, or R^(2a)and R^(2b) may together form ═O or ═NH; R³ an R¹² are each,independently, selected from the group consisting of H, halogen,OR^(4b), -G-J, and N(R^(8a))₂; R^(4a) is selected from the groupconsisting of H, and alkyl; R^(4b) is selected from the group consistingof alkyl and —(CH₂—CH₂—O—)_(n)—R⁹, wherein n is an integer of 1-500,1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000,50,000, or 60,000 or is a mean of a plurality of integers having a valueof 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000,40,000, 50,000, or 60,000; R⁵ is selected from the group consisting ofH, alkyl, and R^(4b); R⁸ is selected from the group consisting of H, CN,NO₂, alkyl, cycloalkyl, and SO₂-alkyl; R^(8a) is absent, or selectedfrom the group consisting of H, -(alkyl)-, -(cycloalkyl)-, C(alkyl)₂-J,—R^(4b), wherein R^(8a) can also cyclize with the atom to which R^(8a)is bonded to form a 3, 4, 5, 6 or 7-membered ring that is aromatic ornon-aromatic and may contain one or more heteroatoms, wherein the ringmay be further substituted one or more times with substitutents that arethe same or different; and R⁹ is selected from the group consisting ofH, alkyl and CH₂CO₂H.
 2. The compound of claim 1, wherein R^(2b), R^(4b)and R⁵ are H, and R^(4a) is CH₃.
 3. The compound of claim 1, whereinR^(2b), R^(4b) and R⁵ are H, R^(4a) is CH₃, and R¹² is CH₂—O—CH₃.
 4. Thecompound of claim 1, wherein formula I is represented by a compound offormula II:

and pharmaceutically acceptable salts thereof.
 5. A compound of theformula III:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof; wherein R^(2a), R^(2b), R³,R^(4a), R^(4b), R⁵, R¹², A, G and J have the meanings set forth forformula I; and ring L is selected form the group consisting ofcycloalkyl, heterocycle, aryl and heteroaryl, all of which may befurther optionally substituted with -A-G-J.
 6. The compound of claim 5,wherein R^(2b), R^(4b) and R⁵ are H, and R^(4a) is CH₃.
 7. The compoundof claim 5, wherein R^(2b), R^(4b) and R⁵ are H, R^(4a) is CH₃, and R¹²is CH₂—O—CH₃.
 8. The compound of claim 5, wherein formula III isrepresented by a compound of formula IV:

and pharmaceutically acceptable salts thereof wherein ring L, A, G and Jhave the meanings set forth for formula III.
 9. A compound of theformula V:

wherein A-G-J is R^(1a); wherein R¹, R^(1a) and R^(2a) are each,independently, selected from the group consisting of H, substituted orunsubstituted alkyl, alkyl-aryl, heteroalkyl, heterocyclyl, heteroaryl,aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy,aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino,alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino,cycloalkylamino, carboxyalkylamino, arlylalkyloxy and heterocyclylamino;all of which may be further independently substituted one or more timeswith Z¹ and Z²; wherein Z¹ is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino,alkylheteroaryl, or heteroarylalkyl; wherein Z¹ can be independentlysubstituted with one or more of Z² moieties which can be the same ordifferent and are independently selected; wherein Z² is hydroxy, alkyl,aryl, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino,arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, keto, esteror nitro; wherein each of said alkyl, alkoxy, and aryl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different and are independentlyselected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl,arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl andheteroarylalkyl; or R¹ and R^(1a) may together form a 3, 4, 5, 6 or7-membered ring that is aromatic or non-aromatic and may contain one ormore heteroatoms, wherein the ring may be further substituted one ormore times with substitutents that are the same or different.
 10. Thecompound of claim 1, wherein R¹ is H or CH₃, and A-G-J together form H,or together form a functional group selected from the group consistingof


11. The compound of claim 1, wherein R¹ is H, and A-G-J together form afunctional group selected from the group consisting of

wherein R¹³ is selected from the group consisting of hydrogen,hydroxymethyl, and aminomethyl or from the group consisting of:

wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000,10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of aplurality of integers having a value of 1-500, 1,000, 2,000, 3,000,4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000.
 12. Thecompound of claim 9, wherein R^(2a) is OH or OAc.
 13. The compound ofclaim 1, wherein the core pyridine functionality is of the followingN-oxide formula:


14. A compound of claim 1, wherein when J is not F, J is bonded to O orN.
 15. A compound claim 1, wherein when R^(b) is not F, R^(a) is —(R¹)₂.16. A compound of the formula VI:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof; wherein R is-(heteroaryl)-A-G-Q-J; A is a bond or is selected from the groupconsisting of —C(O)—, —C(O)C(O)—, —C(O)O—, —C(O)N(R^(8a))—, —S(O)₂—,—S(O)—, —S(O)₂N(R^(8a))—, —S(O)N(R^(8a))—, —C(═NR⁸)N(R^(8a))—,—C(═NR⁸)N(R^(8a))C(O)—, —C(═NR⁸)—, —C═C—C(O)—, —C═C—C(O)O—,—C═C—C(O)N(R^(8a))—; G is absent, selected from the group consisting of—[C(R^(a))(R^(b))]_(x)—,—[C(R^(a))(R^(b))]_(x)—C(R^(a))═C(R^(a))—[C(R^(a))(R^(b))]_(y)—,—[C(R^(a))(R^(b))]_(x)—O—[C(R^(a))(R^(b))]_(y)—, and—[C(R^(a))(R^(b))]_(x)—N(R^(8a))—[C(R^(a))(R^(b))]_(y)—, or is selectedfrom the group consisting of -(cycloalkyl)-, -(heterocycle)-, -(aryl)-,and -(heteroaryl)- each of which has 0-4 substituents; Q is absent,selected from the group consisting of —C(O)—[C(R^(a))(R^(b))]_(x)—,—C(O)—[C(R^(a))(R^(b))]_(x)—C(R^(a))═C(R^(a))—[C(R^(a))(R^(b))]_(y)—,—C(O)—[C(R^(a))(R^(b))]_(x)—O—[C(R^(a))(R^(b))]_(y)—, and—C(O)—{N(R^(8a))—[C(R^(a))(R^(b))]_(y)}_(p)—, or is selected from thegroup consisting of -(cycloalkyl)-, -(heterocycle)-, -(aryl)-,-(heteroaryl)-, —C(O)-(cycloalkyl)-, —C(O)-(heterocycle)-,—C(O)-(aryl)-, and —C(O)-(heteroaryl)-, each of which has 0-4substituents; J is selected from the group consisting of H, C₁₋₄alkyl,halogen, C₁₋₄alkoxy, hydroxy, amino, mono- and di-C₁₋₄alkylamino,triC₁₋₄alkylammonium, N(R^(8a))C(O)C₁₋₄alkyl, CO₂H, C(═O)N(R^(8a))₂,CH₂CO₂H, CH₂C(═O)N(R^(8a))₂, CO₂—C₁₋₄alkyl, C(O)C₁₋₄alkyl, P(O)(OH)₂,P(O)(O—C₁₋₄alkyl)₂, C₀₋₄alkylene-(cycloalkyl) andC₀₋₄alkylene-(heterocycle), which heterocycle may be substituted 0-4times; R^(a) is selected from the group consisting of H, alkyl, F, CO₂H,CO₂-alkyl, —N(R¹)₂, —OR¹, —(CH₂)₀₋₄-J and —R^(4b); R^(b) is selectedfrom the group consisting of H, alkyl, and F; p is 0, 1, 2, or 3; x andy are each, independently selected at each occurrence from integers from0-10; R² is hydrogen, C₁₋₆-alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₀₋₆alkyl,C₃₋₇cycloalkylC₀₋₄alkyl, arylC₀₋₄alkyl, or a residue of the formula:

R^(2a) is selected from the group consisting of H, C₁₋₆alkyl, OH,OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ and N(R^(8a))₂; R^(2b) is H orC₁₋₆alkyl, or R^(2a) and R^(2b) taken in combination form an oxo orimino group; R³ and R¹² are each, independently, selected from the groupconsisting of H, halogen, OR^(4b), -G-J, and N(R^(8a))₂; R^(4a) isselected from the group consisting of H and alkyl; R^(4b) is selectedfrom the group consisting of alkyl and —(CH₂—CH₂—O—)_(n)—R⁹, wherein nis an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000,20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality ofintegers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000,10,000, 20,000, 30,000, 40,000, 50,000, or 60,000; R⁵ is selected fromthe group consisting of H, alkyl, and R^(4b); R⁸ is selected from thegroup consisting of H, CN, NO₂, C₁₋₆alkyl, C₃₋₇cycloalkyl, andSO₂—C₁₋₆alkyl; R^(8a) is absent, or selected from the group consistingof H, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyl substituted with J, andR^(4b), or two R^(8a) residues, taken in combination may form asaturated, unsaturated or aromatic ring having 3 to 7 ring atoms, whichring may be substituted 0-4 times; and R⁹ is selected from the groupconsisting of H, alkyl and CH₂CO₂H.
 17. The compound of claim 16,wherein R² is a residue of the formula:

R^(2a) is selected from the group consisting of H, C₁₋₆alkyl, OH,OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ and N(R^(8a))₂; and R^(2b) is H orC₁₋₆alkyl, or R^(2a) and R^(2b) taken in combination form an oxo orimino group.
 18. The compound of claim 16, wherein R^(2b), R^(4b) and R⁵are H, and R^(4a) is CH₃.
 19. The compound of claim 16, wherein R^(2b),R^(4b) and R⁵ are H, R^(4a) is CH₃, and R¹² is CH₂—O—CH₃. 20-21.(canceled)
 22. The compound of claim 16, wherein R^(2a) is OH or OAc andR^(2b) is H.
 23. The compound of claim 16, wherein A is C(O), C(O)O, orC(O)NH; G is C₄₋₇cycloalkyl; Q is absent; and J is CO₂H or CO₂C₁₋₄alkyl.24. The compound of claim 16, wherein formula VI is represented by acompound of formula VII:

and pharmaceutically acceptable salts thereof.
 25. A compound of theformula VIII:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including the pyridine N-oxide thereof; wherein

is a 4-7 membered heteroaryl ring having 0-2 additional ring heteroatomswhich is substituted with a -A-G-Q-J residue and 0-4 additionalsubstituents; A is a bond or is selected from the group consisting of—C(O)—, —C(O)C(O)—, —C(O)O—, —C(O)N(R^(8a))—, —S(O)₂—, —S(O)—,—S(O)₂N(R^(8a))—, —S(O)N(R^(8a))—, —C(═NR⁸)N(R^(8a))—,—C(═NR⁸)N(R^(8a))C(O)—, —C(═NR⁸)—, —C═C—C(O)—, —C═C—C(O)O—,—C═C—C(O)N(R^(8a))—; G is absent, selected from the group consisting of—[C(R^(a))(R^(b))]_(x)—,—[C(R^(a))(R^(b))]_(x)—C(R^(a))═C(R^(a))—[C(R^(a))(R^(b))]_(y)—,—[C(R^(a))(R^(b))]_(x)—O—[C(R^(a))(R^(b))]_(y)—, and—[C(R^(a))(R^(b))]_(x)—N(R^(8a))—[C(R^(a))(R^(b))]_(y)—, or is selectedfrom the group consisting of -(cycloalkyl)-, -(heterocycle)-, -(aryl)-,and -(heteroaryl)- each of which has 0-4 substituents; Q is absent,selected from the group consisting of —C(O)—[C(R^(a))(R^(b))]_(x)—,—C(O)—[C(R^(a))(R^(b))]_(x)—C(R^(a))═C(R^(a))—[C(R^(a))(R^(b))]_(y)—,—C(O)—[C(R^(a))(R^(b))]_(x)—O—[C(R^(a))(R^(b))]_(y)—, and—C(O)—{N(R^(8a))—[C(R^(a))(R^(b))]_(y)}_(p)—, or is selected from thegroup consisting of -(cycloalkyl)-, -(heterocycle)-, -(aryl)-,-(heteroaryl)-, —C(O)-(cycloalkyl)-, —C(O)-(heterocycle)-,—C(O)-(aryl)-, and —C(O)-(heteroaryl)-, each of which has 0-4substituents; J is selected from the group consisting of H, C₁₋₄alkyl,halogen, C₁₋₄alkoxy, hydroxy, amino, mono- and di-C₁₋₄alkylamino,triC₁₋₄alkylammonium, N(R^(8a))C(O)C₁₋₄alkyl, CO₂H, C(═O)N(R^(8a))₂,CH₂CO₂H, CH₂C(═O)N(R^(8a))₂, CO₂—C₁₋₄alkyl, C(O)C₁₋₄alkyl, P(O)(OH)₂,P(O)(O—C₁₋₄alkyl)₂, C₀₋₄alkylene-(cycloalkyl) andC₀₋₄alkylene-(heterocycle), which heterocycle may be substituted 0-4times; R^(a) is selected from the group consisting of H, alkyl, F, CO₂H,CO₂-alkyl, —N(R¹)₂, —OR¹, —(CH₂)₀₋₄-J and —R^(4b); R^(b) is selectedfrom the group consisting of H, alkyl, and F; p is 0, 1, 2, or 3; x andy are each, independently selected at each occurrence from integers from0-10; R¹ is independently selected at each occurrence from —H, alkylsubstituted with J, and —R^(4b); R² is hydrogen, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₀₋₆alkyl, C₃₋₇cycloalkylC₀₋₄alkyl,arylC₀₋₄alkyl, or a residue of the formula:

R^(2a) is selected from the group consisting of H, C₁₋₆alkyl, OH,OR^(4a), OC(O)R^(4a), OC(O)N(R^(8a))₂ and N(R^(8a))₂; R^(2b) is H orC₁₋₆alkyl, or R^(2a) and R^(2b) taken in combination form an oxo orimino group; R³ and R¹² are each, independently, selected from the groupconsisting of H, halogen, OR^(4b), -G-J, and N(R^(8a))₂; R^(4a) isselected from the group consisting of H and alkyl; R^(4b) is selectedfrom the group consisting of alkyl and —(CH₂—CH₂—O—)_(n)—R⁹, wherein nis an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000,20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality ofintegers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000,10,000, 20,000, 30,000, 40,000, 50,000, or 60,000; R⁵ is selected fromthe group consisting of H, alkyl, and R^(4b); R⁸ is selected from thegroup consisting of H, CN, NO₂, C₁₋₆alkyl, C₃₋₇cycloalkyl, andSO₂—C₁₋₆alkyl; R^(8a) is absent, or selected from the group consistingof H, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyl substituted with J, andR^(4b), or two R^(8a) residues, taken in combination may form asaturated, unsaturated or aromatic ring having 3 to 7 ring atoms, whichring may be substituted 0-4 times; and R⁹ is selected from the groupconsisting of H, alkyl and CH₂CO₂H.
 26. The compound of claim 25,wherein R² is a residue of the formula:

R^(2a) is selected from the group consisting of H, OH, OR^(4a),OC(O)R^(4a), OC(O)N(R^(8a))₂ and N(R^(8a))₂; and R^(2b) is H orC₁₋₆alkyl, or R^(2a) and R^(2b) taken in combination form an oxo orimino group.
 27. The compound of claim 25, wherein R^(2b), R^(4b) and R⁵are H, and R^(4a) is CH₃.
 28. The compound of claim 25, wherein R^(2b),R^(4b) and R⁵ are H, R^(4a) is CH₃, and R¹² is CH₂—O—CH₃.
 29. Thecompound of claim 25, wherein

is an imidazolyl ring; and A-G-Q-J together form H, or together form afunctional group selected from the group consisting of


30. The compound of claim 25, wherein

is an imidazolyl ring; and A-G-Q-J together form a functional groupselected from the group consisting of

wherein R¹³ is selected from the group consisting of hydrogen,hydroxymethyl, and aminomethyl or from the group consisting of:

n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000,20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality ofintegers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000,10,000, 20,000, 30,000, 40,000, 50,000, or 60,000.
 31. The compound ofclaim 25, wherein R^(2a) is OH or OAc and R^(2b) is H.
 32. (canceled)33. A method of treating a bacterial infection comprising administeringto a subject in need thereof a pharmaceutically acceptable amount of acompound of claim 1 such that the bacterial infection is treated. 34.(canceled)
 35. A method of treating, inhibiting or preventing theactivity of EF-Tu in a subject in need thereof, comprising administeringto the subject a pharmaceutically acceptable amount of a compound ofclaim
 1. 36. The method of claim 35, wherein a bacterial infection istreated in a subject in need thereof. 37-39. (canceled)
 40. A method oftreating a bacterial infection comprising administering to a subject inneed thereof a pharmaceutically effective amount of a compound claim 1in combination with a pharmaceutically effective amount of an additionaltherapeutic agent, such that the bacterial infection is treated.
 41. Themethod of claim 40 wherein the compound of claim 1 and the otherpharmaceutical agent are administered as part of the same pharmaceuticalcomposition.
 42. The method of claim 40 wherein the compound of claim 1and the other therapeutic agent are administered as separatepharmaceutical compositions, and the compound is administered prior to,at the same time as, or following administration of the other agent. 43.(canceled)
 44. A method of treating acne in subject in need thereofcomprising administering to the subject a pharmaceutically acceptableamount of a compound of claim
 1. 45. A pharmaceutical compositioncomprising a compound of claim 1 and at least one pharmaceuticallyacceptable carrier or diluent.
 46. A method of treating a bacterialinfection comprising administering to a subject in need thereof apharmaceutically acceptable amount of a compound of claim 16 such thatthe bacterial infection is treated.
 47. A method of treating, inhibitingor preventing the activity of EF-Tu in a subject in need thereof,comprising administering to the subject a pharmaceutically acceptableamount of a compound of claim
 16. 48. A method of treating a bacterialinfection comprising administering to a subject in need thereof apharmaceutically effective amount of a compound of claim 16 incombination with a pharmaceutically effective amount of an additionaltherapeutic agent, such that the bacterial infection is treated.
 49. Themethod of claim 40 wherein the compound of claim 16 and the otherpharmaceutical agent are administered as part of the same pharmaceuticalcomposition.
 50. The method of claim 40 wherein the compound of claim 16and the other therapeutic agent are administered as separatepharmaceutical compositions, and the compound is administered prior to,at the same time as, or following administration of the other agent. 51.A method of treating acne in subject in need thereof comprisingadministering to the subject a pharmaceutically acceptable amount of acompound of claim
 16. 52. A pharmaceutical composition comprising acompound of claim 16 and at least one pharmaceutically acceptablecarrier or diluent.
 53. The compound of claim 5 wherein R¹ is H, andA-G-J together form a functional group selected from the groupconsisting of

wherein R¹³ is selected from the group consisting of hydrogen,hydroxymethyl, and aminomethyl or from the group consisting of:

wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000,10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of aplurality of integers having a value of 1-500, 1,000, 2,000, 3,000,4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000.
 54. Thecompound of claim 9 wherein R¹ is H, and A-G-J together form afunctional group selected from the group consisting of

wherein R¹³ is selected from the group consisting of hydrogen,hydroxymethyl, and aminomethyl or from the group consisting of:

wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000,10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of aplurality of integers having a value of 1-500, 1,000, 2,000, 3,000,4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000.